CN103800913A - Composition capable of eliminating clouding formation phenomenon of TPGS and application thereof in medicinal preparation - Google Patents

Abstract

The present invention is a composition capable of eliminating TPGS twilight phenomenon and its application in pharmaceutical preparations. It includes insoluble drug, TPGS, polyoxyethylene polyoxypropylene copolymer and/or polyoxyethylene castor oil, polyol and water, in which insoluble drug: TPGS: polyoxyethylene polyoxypropylene copolymer: polyol The weight ratio is 0.001-2:1:0.5-5:2-20, and the balance is water. When this combination is used in the preparation of common insoluble drug injections, the obtained preparation can withstand sterilization at 100°C for 30 minutes and 121°C for 8 minutes without any cloudy phenomenon, ensuring the controllability of the entire preparation process. The present invention The disclosed combination eliminates the twilight phenomenon of TPGS, and solves the serious problem existing in the application of TPGS in large-scale industrial production.

Description

Composition capable of eliminating TPGS twilight phenomenon and its application in pharmaceutical preparations

technical field

The invention belongs to the field of pharmaceutical preparations, and relates to a combination capable of eliminating TPGS flash phenomenon and its application in pharmaceutical preparations.

Background technique

α-tocopheryl polyethylene glycol (PEG) 1000 succinate, or TPGS, is obtained from the esterification reaction of α-tocopheryl succinate and PEG1000, containing tocopheryl lipophilic groups and polyethylene glycol long chains The hydrophilic group is a non-ionic surfactant that has been listed in the United States Pharmacopoeia. Its average molecular weight is about 1513, and its structural formula is as follows:

TPGS was first produced and marketed by Eastman Company of the United States in 1950. It was discovered in 1960 that it could be used as a solubilizer, and then reports on its toxicity and safety also appeared. In the 1980s, TPGS was used to treat tocopherol deficiency. After that, more and more researches focused on its own characteristics and applications, especially as an absorption enhancer for poorly absorbed substances such as cyclamen and vitamin D, and a hemostatic agent carrier. It has been researched and produced continuously for many years. At present, amprenavir oral liquid and capsules with TPGS as auxiliary materials have been listed in the United States.

Due to its amphiphilicity and good water solubility, TPGS is a good solubilizer for lipophilic substances. When it forms micelles or emulsions with poorly soluble drugs, it can significantly improve the absorption of drugs in the gastrointestinal tract. Compared with other surfactants, TPGS also has antioxidant effect, which is more conducive to improving the stability of the preparation.

It can be inferred that TPGS will become a new generation of high-efficiency and low-toxicity surfactant in the near future. It will have very broad application prospects in solubilizers, emulsifiers, carriers of fat-soluble drug delivery systems, and the like.

Although TPGS has many of the above advantages, it also has extremely serious disadvantages, that is, there is a hydrophilic polyoxyethylene segment-polyethylene glycol in the structure of TPGS that limits its wide application in high-temperature sterilization preparations.

In the anhydrous state, the polyoxyethylene chain in TPGS is in a zigzag state, and the oxygen atom on the ether bond dissolved in hydration forms a weak hydrogen bond with the hydrogen atom in the water, and the molecular chain is zigzag, hydrophilic The oxygen atom is located on the outside of the chain, while the ethylene group (—CH2CH2—) is located on the inside of the chain, so the surrounding chain is like a hydrophilic whole. the

Because the reaction to form hydrogen bonds is exothermic, and the hydrogen bonding force is weak, when the temperature rises, the TPGS aqueous solution will weaken the hydrophilicity due to the destruction of the combined hydrogen bonds, thus changing from the original The clear solution turned into a white cloudy emulsion.

If it is in large-scale industrial production, the serious consequences that may be caused by the phenomenon of TPGS clouding are: when a batch or even several batches of injections that use TPGS as a solubilizer are sterilized, the preparations will be scrapped due to clouding, which will not only cause labor costs for the enterprise Multiple unnecessary losses of material resources, financial resources, etc., and also lead to uncontrollable process and randomness of qualified preparations in the preparation process of TPGS-related sterilization preparations.

In addition, the serious consequences of the phenomenon of TPGS twilight may also lead to a greatly reduced application prospect.

Contents of the invention

For the above-mentioned serious problem that TPGS exists - the twilight phenomenon, the purpose of the present invention is to screen the combination that can eliminate the TPGS twilight phenomenon and use this combination for the preparation of fat-soluble drug sterilization preparations with TPGS as a solubilizing agent.

In order to realize the purpose of the present invention, the inventor provides the following technical solutions:

A combination that can eliminate the phenomenon of TPGS clouding and its application in fat-soluble drug sterilization preparations that use TPGS as a solubilizer.

The combination provided by the present invention that can eliminate the phenomenon of TPGS flashing includes insoluble drugs, TPGS, polyoxyethylene polyoxypropylene copolymer and or polyoxyethylene (hydrogenated) castor oil, polyols and water.

Insoluble drugs in the combination of the present invention should include coenzyme Q ₁₀ , fat-soluble vitamins (A, D, E, K), nimodipine, ginsenosides, alprostadil, cyclic adenosine monophosphate, acyclovir, Paclitaxel, docetaxel, hydroxycamptothecin, ribavirin, cucurbitacin, etc. are poorly water-soluble drugs that can be expanded with TPGS.

The inventor found that coenzyme Q ₁₀ , fat-soluble vitamins (A, D, E, K), ginsenosides, alprostadil, cyclic adenosine monophosphate, acyclovir, paclitaxel, docetaxel, Ribavirin, nimodipine, cucurbitacin and other injections, when these injections were sterilized at 100°C for 30 minutes and 121°C for 8 minutes, no clouding phenomenon occurred.

The polyoxyethylene-polyoxypropylene copolymer of the present invention has a structural formula of EOn-POm-EOn, which is an ABA-type tri-block copolymer, and is a new type of polymer nonionic surfactant. Theoretically, there can be countless kinds of compounds with such a basic structure, and their molecular weights range from 1000 to 7000 or more. An appropriate amount of polyoxypropylene and an appropriate amount of polyoxyethylene are copolymerized into compounds with different hydrophilic-lipophilic balance values. Preferably, it is defined as EO ₇₆ -PO ₃₀ -EO ₇₆ , that is, Pluronic 188 (F68).

The polyoxyethylene (hydrogenated) castor oil described in the present invention includes polyoxyethylene 40 hydrogenated castor oil (RH40), castor oil polyhydroxylate 35 (Cremophor EL), castor oil polyhydroxylate 35 (purified grade) (Cremophor ELP).

When the combination of the present invention is composed of insoluble drugs, TPGS, polyoxyethylene polyoxypropylene copolymers, polyols and water, wherein insoluble drugs: TPGS: polyoxyethylene polyoxypropylene copolymers: polyols: The weight ratio of water is 0.001-2:1:0.5-5:2-20, and the balance is water.

When the combination of the present invention is composed of insoluble drugs, TPGS, polyoxyethylene (hydrogenated) castor oil, polyols and water, in which insoluble drugs: TPGS: polyoxyethylene (hydrogenated) castor oil: polyols: The weight ratio of water is 0.001-2: 1: 0.5-5: 2-20: 30-50, preferably, the weight ratio of insoluble drugs: TPGS: polyoxyethylene (hydrogenated) castor oil: polyol: water is 0.001-2:1:1-4:3-15:30-50, as more preferred, poorly soluble drugs: TPGS: polyoxyethylene (hydrogenated) castor oil: polyol weight ratio is 0.001-2:1:1.5 -4: 3-10, the balance is 30-50 of water.

When the combination of the present invention consists of insoluble drugs, TPGS, polyoxyethylene polyoxypropylene copolymer and polyoxyethylene hydrogenated castor oil (castor oil), polyol and water. , of which insoluble drugs: TPGS: polyoxyethylene polyoxypropylene copolymer and polyoxyethylene hydrogenated castor oil (castor oil): polyol: water weight ratio is 0.001-2:1:0.5-5:2-20 : 30-50, as preferred, poorly soluble drugs: TPGS: polyoxyethylene polyoxypropylene copolymer and polyoxyethylene hydrogenated castor oil (castor oil): polyol: water with a weight ratio of 0.001-2:1:1 -4:3-15:30-50, as more preferred, insoluble drugs: TPGS: polyoxyethylene polyoxypropylene copolymer and polyoxyethylene hydrogenated castor oil (castor oil): polyol weight ratio of 0.001-2 :1:1.5-4:3-10, the balance is water.

The polyhydroxy compound of the present invention includes glucose, xylose, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, maltitol, propylene glycol, glycerin, PEG200, PEG300, PEG400, PEG600 , PEG1000, PEG2000, PEG4000, PEG6000, etc., or a mixture of several of them; preferably, the polyhydroxy compound in the composition is defined as xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, Glycerin, PEG200, PEG300, PEG400, PEG600; As more preferably, the polyol in the composition is defined as propylene glycol, glycerin, PEG300, PEG400.

The water described in the present invention can be one of purified water, distilled water, water for injection, sterilized purified water, sterilized water for injection and the like. As a preferred version, the water described in the present invention is sterilized purified water or sterilized water for injection.

The inventor's research also found that coenzyme Q 10 , fat-soluble coenzyme Q ₁₀ , fat-soluble Vitamins (A, D, E, K), ginsenosides, alprostadil, cyclic adenosine monophosphate, acyclovir, paclitaxel, docetaxel, hydroxycamptothecin, ribavirin, nimodipine, cucurbitacin When other injections are sterilized at 100°C for 30 minutes and 121°C for 8 minutes, the preparations will become turbid, and some of the preparations will also precipitate colloidal precipitates, which show a very obvious phenomenon of blurring. And only when the polyhydroxy compound in the combination of the present invention is used in combination with polyoxyethylene polyoxypropylene copolymer and or polyoxyethylene (hydrogenated) castor oil, the above-mentioned injection prepared with TPGS as a solubilizer, After sterilizing at 100°C for 30 minutes and at 121°C for 8 minutes, there was no clouding phenomenon.

The present invention also provides the application of the above-mentioned combination capable of eliminating the phenomenon of TPGS twilight in the oral liquid of poorly soluble drugs using TPGS as a solubilizer.

The present invention also provides the application of the above-mentioned combination capable of eliminating the phenomenon of TPGS blurring in an emulsion for injection of insoluble drugs using TPGS as an emulsifier.

The present invention also provides the application of the above-mentioned combination capable of eliminating the phenomenon of TPGS twitching in an oral emulsion of insoluble drugs using TPGS as an emulsifier.

The present invention proposes for the first time a solution to eliminate the phenomenon of TPGS flashing, and pays attention to the flashing phenomenon of TPGS that is easily overlooked by everyone in actual production and application, but has a great risk, so that the pharmaceutical preparations related to TPGS that need to be sterilized can be used in industrial production. , which effectively conforms to the controllability of each step of the process and the uniformity and safety of the preparation, avoiding the complete unusability of one batch or even several batches of preparations that may be caused by the flash phenomenon, the content of the preparation before and after sterilization, particle size and particle size The occurrence of various negative consequences such as large changes in the distribution.

Detailed ways

In order to understand the present invention more clearly, the present invention will be further described in detail below in combination with the embodiments provided by the inventors and completed according to the technical solution of the present invention.

The following are the embodiments given by the inventor, the present invention is not limited to these embodiments, and any modifications and/or changes made to the present invention will fall within the protection scope of the present invention.

Example 1: Preparation of coenzyme Q ₁₀ injection solubilized with TPGS alone

Prescription 1:

Coenzyme Q ₁₀ 75 mg

                                    600 mg

  Water for Injection             28 mL

            

            

30 mL

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all yellow transparent solutions.

Observation after sterilization: the preparation became turbid, and wine-red jelly was precipitated at the bottom of the bottle, indicating that TPGS did have obvious flashing phenomenon.

Embodiment 2 : Preparation of Coenzyme Q ₁₀ Injection without Sudden Phenomena Solubilized by TPGS (fixed TPGS: F68=1:1 (m/m), polyol selects different amounts of propylene glycol)

prescription:

the Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ and TPGS to form the oil phase; weigh the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 3: Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: F68=1:3(m/m), Different Amounts of Glycerin are Selected as Polyols)

prescription:

the Prescription 8 Prescription 9 Prescription 10 Prescription 11 Prescription 12 Prescription 13 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ and TPGS to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and there is no phenomenon of blurring in the preparations.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS.

Embodiment 4 : Preparation of Coenzyme Q ₁₀ Injection without Sudden Phenomena Solubilized with TPGS (fixed TPGS: RH40=1:1 (m/m), polyols select different amounts of propylene glycol)

prescription:

the Prescription 14 Prescription 15 Prescription 16 Prescription 17 Prescription 18 Prescription 19 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ , TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and there is no phenomenon of blurring in the preparations.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 5: Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS without Suffering Phenomenon (fixed TPGS: RH40=1:3(m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 20 Prescription 21 Prescription 22 Prescription 23 Prescription 24 Prescription 25 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ , TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and there is no phenomenon of blurring in the preparations.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 6 : Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS (Fixed TPGS: (F68+RH40) = 1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 26 Prescription 27 Prescription 28 Prescription 29 Prescription 30 Prescription 31 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ , TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 7: Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: (F68+RH40)=1:3(m/m), Different Amounts of Glycerol for Polyols)

prescription:

the Prescription 32 Prescription 33 Prescription 34 Prescription 35 Prescription 36 Prescription 37 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ , TPGS, and RH40 to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 8: Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS with Sudden Phenomenon (without adding F68 and RH40, using different amounts of polyol PEG400 alone)

prescription:

the Prescription 38 Prescription 39 Prescription 40 Prescription 41 Prescription 42 Prescription 43 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg PEG400 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ and TPGS to form the oil phase; weigh the prescribed amount of PEG400 and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately observe the state of the preparation after sterilization: the preparations obtained from the above six prescriptions all become turbid to varying degrees, and wine-red jelly precipitates at the bottom of the bottle, that is, HS15 becomes dark when it is sterilized at 100°C for 30 minutes and 121°C for 8 minutes. , The jelly did not return to the dissolved state after standing at room temperature.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, glycerin, PEG200, PEG300, PEG600 instead of PEG400 to get consistent experimental results, that is, using different amounts of polyols alone cannot eliminate the cause of TPGS Epiphany.

Example 9: Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS with Sudden Phenomenon (without adding polyols, using different amounts of F68 alone)

prescription:

the Prescription 44 Prescription 45 Prescription 46 Prescription 47 Prescription 48 Prescription 49 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 900mg 1200mg 1800mg 2100mg 2400mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ and TPGS to form the oil phase; weigh the prescribed amount of F68 and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Observe the state of the preparation immediately after sterilization:

The preparations obtained from the above six prescriptions all became turbid to varying degrees, and wine-red jelly was precipitated at the bottom of the bottle, that is, when HS15 was sterilized at 100°C for 30 min and 121°C for 8 min, the jelly appeared. Did not return to solution.

That is to say, using F68 alone cannot eliminate the phenomenon of TPGS.

Example 10: Preparation of Coenzyme Q ₁₀ Injection Solubilized with TPGS with Suffering Phenomena (without adding polyols, using different amounts of RH40 alone)

prescription:

the Prescription 50 Prescription 51 Prescription 52 Prescription 53 Prescription 54 Prescription 55 Coenzyme Q ₁₀ 75mg 75mg 75mg 75mg 75mg 75mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 300mg 600mg 900mg 1200mg 1800mg 2400mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of coenzyme Q ₁₀ , TPGS, and RH40 to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the formulations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Observe the state of the preparation immediately after sterilization:

The preparations obtained from the above six prescriptions all became turbid to varying degrees, and wine-red jelly was precipitated at the bottom of the bottle, that is, when HS15 was sterilized at 100°C for 30 min and 121°C for 8 min, the jelly appeared. Did not return to solution.

That is to say, using RH40 alone cannot eliminate the phenomenon of TPGS.

Example 11: Preparation of vitamin K1 injection solubilized with TPGS alone

Prescription 56:

                                                                                                                , 

TPGS 600 mg

Water for Injection 28 mL

            

            

30 mL

Process:

Weigh the prescribed amount of vitamin K1 and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all yellow transparent solutions.

Observation after sterilization: the preparation became turbid, and wine-red jelly was precipitated at the bottom of the bottle, indicating that TPGS did have obvious flashing phenomenon.

Embodiment 12 : Preparation of Vitamin K1 Injection without Sudden Phenomena Solubilized with TPGS (Fixed TPGS: F68=1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 57 Prescription 58 Prescription 59 Prescription 60 Prescription 61 Prescription 62 Vitamin K1 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of vitamin K1 and TPGS to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 13: Preparation of Vitamin K1 Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: F68=1:3(m/m), Different Amounts of Glycerin for Polyols)

prescription:

the Prescription 63 Prescription 64 Prescription 65 Prescription 66 Prescription 67 Prescription 68 Vitamin K1 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of vitamin K1 and TPGS to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS flashing.

Embodiment 14 : Preparation of Vitamin K1 Injection without Sudden Phenomena Solubilized with TPGS (fixed TPGS: RH40=1:1 (m/m), polyols select different amounts of propylene glycol)

prescription:

the Prescription 69 Prescription 70 Prescription 71 Prescription 72 Prescription 73 Prescription 74 Vitamin K1 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of vitamin K1, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 15: Preparation of Vitamin K1 Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: RH40=1:3(m/m), Different Amounts of Glycerin for Polyols)

prescription:

the Prescription 75 Prescription 76 Prescription 77 Prescription 78 Prescription 79 Prescription 80 Vitamin K1 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of vitamin K1, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 16 : Preparation of Vitamin K1 Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: (F68+RH40)=1:1 (m/m), different amounts of propylene glycol are selected for polyols)

prescription:

the Prescription 81 Prescription 82 Prescription 83 Prescription 84 Prescription 85 Prescription 86 Vitamin K1 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of vitamin K1, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 17: Preparation of Vitamin K1 Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: (F68+RH40) = 1:3 (m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 87 Prescription 88 Prescription 89 Prescription 90 Prescription 91 Prescription 92 Vitamin K1 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of vitamin K1, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all yellow transparent solutions.

Immediately after sterilization, observe the state of the preparations: they are all yellow transparent solutions, and the preparations do not appear to have any epilepsy.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Embodiment 18: Preparation of Alprostadil injection with TPGS solubilization alone

Prescription 93:

                                  6 mg

TPGS 600 mg

  Water for Injection                                          

            

            

30 mL

Process:

Weigh the prescribed amount of alprostadil and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all colorless transparent solutions.

Observation after sterilization: the preparation became turbid, and jelly-like substances were precipitated at the bottom of the bottle, indicating that TPGS did have obvious clouding phenomenon.

Embodiment 19 : Preparation of Alprostadil Injection without twitching phenomenon of TPGS solubilization (fixed TPGS: F68=1:1 (m/m), polyol selects different amounts of propylene glycol)

prescription:

the Prescription 94 Prescription 95 Prescription 96 Prescription 97 Prescription 98 Prescription 99 Alprostadil 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of alprostadil and TPGS to form the oil phase; weigh the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 20: Preparation of Alprostadil Injection Solubilized with TPGS (Fixed TPGS: F68=1:3(m/m), Different Amounts of Glycerin for Polyols)

prescription:

the Prescription 100 Prescription 101 Prescription 102 Prescription 103 Prescription 104 Prescription 105 Alprostadil 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of alprostadil and TPGS to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS.

Embodiment 21 : Preparation of Alprostadil Injection without Sudden Phenomena of TPGS Solubilization (Fixed TPGS: RH40=1:1 (m/m), polyol selects different amounts of propylene glycol)

prescription:

the Prescription 106 Prescription 107 Prescription 108 Prescription 109 Prescription 110 Prescription 111 Alprostadil 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of alprostadil, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 22: Preparation of Alprostadil Injection Solubilized with TPGS (Fixed TPGS: RH40=1:3(m/m), Different Amounts of Glycerin for Polyols)

prescription:

the Prescription 112 Prescription 113 Prescription 114 Prescription 115 Prescription 116 Prescription 117 Alprostadil 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of alprostadil, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Embodiment 23 : Preparation of Alprostadil Injection without Sudden Phenomena Solubilized with TPGS (Fixed TPGS: (F68+RH40)=1:1 (m/m), polyol selects different amounts of propylene glycol)

prescription:

the Prescription 118 Prescription 119 Prescription 120 Prescription 121 Prescription 122 Prescription 123 Alprostadil 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of alprostadil, TPGS, and RH40 to form the oil phase; weigh the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 24: Preparation of Alprostadil Injection Solubilized with TPGS without Suffering Phenomenon (fixed TPGS: (F68+RH40)=1:3(m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 124 Prescription 125 Prescription 126 Prescription 127 Prescription 128 Prescription 129 Alprostadil 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of alprostadil, TPGS, and RH40 to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 25: Preparation of cyclic adenosine monophosphate injection solubilized with TPGS alone

Prescription 130:

                                6 mg

TPGS 600 mg

    Water for Injection                                                                              

            

30 mL

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all colorless transparent solutions.

Observation after sterilization: the preparation became turbid, and jelly-like substances were precipitated at the bottom of the bottle, indicating that TPGS did have obvious clouding phenomenon.

Embodiment 26 : Preparation of cyclic adenosine monophosphate injection without bubbling phenomenon solubilized by TPGS (fixed TPGS: F68=1:1 (m/m), polyols select different amounts of propylene glycol)

prescription:

the Prescription 131 Prescription 132 Prescription 133 Prescription 134 Prescription 135 Prescription 136 cyclic adenosine monophosphate 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate and TPGS to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 27: Preparation of Cyclic Adenosine Monophosphate Injection Solubilized with TPGS (Fixed TPGS: F68=1:3(m/m), Different Amounts of Glycerol for Polyols)

prescription:

the Prescription 137 Prescription 138 Prescription 139 Prescription 140 Prescription 141 Prescription 142 cyclic adenosine monophosphate 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate and TPGS to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS flashing.

Embodiment 28 : Preparation of cyclic adenosine monophosphate injection without twilight phenomenon solubilized by TPGS (fixed TPGS: RH40=1:1 (m/m), polyols select different amounts of propylene glycol)

prescription:

the Prescription 143 Prescription 144 Prescription 145 Prescription 146 Prescription 147 Prescription 148 cyclic adenosine monophosphate 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 29: Preparation of Cyclic Adenosine Monophosphate Injection Solubilized with TPGS (Fixed TPGS: RH40=1:3(m/m), Different Amounts of Glycerol for Polyols)

prescription:

the Prescription 149 Prescription 150 Prescription 151 Prescription 152 Prescription 153 Prescription 154 cyclic adenosine monophosphate 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 30 : Preparation of cyclic adenosine monophosphate injection solubilized with TPGS (fixed TPGS: (F68+RH40) = 1:1 (m/m), different amounts of propylene glycol are selected as polyols) solubilized with TPGS

prescription:

the Prescription 155 Prescription 156 Prescription 157 Prescription 158 Prescription 159 Prescription 160 cyclic adenosine monophosphate 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 31: Preparation of cyclic adenosine monophosphate injection solubilized with TPGS without flashing phenomenon (fixed TPGS: (F68+RH40) = 1:3 (m/m), different amounts of glycerin are selected as polyols)

prescription:

the Prescription 161 Prescription 162 Prescription 163 Prescription 164 Prescription 165 Prescription 166 cyclic adenosine monophosphate 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cyclic adenosine monophosphate, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 32: Preparation of ginsenoside injection solubilized with TPGS alone

Prescription 167:

Ginsenosides 60 mg

TPGS 600 mg

  Water for Injection                                          

            

            

30 mL

Process:

Weigh the prescribed amount of ginsenoside and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all colorless transparent solutions.

Observation after sterilization: the preparation became turbid, and jelly-like substances were precipitated at the bottom of the bottle, indicating that TPGS did have obvious clouding phenomenon.

Example 33 : Preparation of Ginsenoside Injection Solubilized with TPGS without Suffering Phenomenon (fixed TPGS: F68=1:1 (m/m), different amounts of propylene glycol are selected for polyols)

prescription:

the Prescription 168 Prescription 169 Prescription 170 Prescription 171 Prescription 172 Prescription 173 Ginsenosides 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ginsenoside and TPGS to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 34: Preparation of Ginsenoside Injection Solubilized with TPGS without Suffering Phenomena (fixed TPGS: F68=1:3(m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 174 Prescription 175 Prescription 176 Prescription 177 Prescription 178 Prescription 179 Ginsenosides 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ginsenoside and TPGS to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS.

Example 35 : Preparation of Ginsenoside Injection Solubilized with TPGS without Sudden Phenomena (fixed TPGS: RH40=1:1 (m/m), polyols are selected with different amounts of propylene glycol)

prescription:

the Prescription 180 Prescription 181 Prescription 182 Prescription 183 Prescription 184 Prescription 185 Ginsenosides 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml up to 30 ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ginsenoside, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 36: Preparation of Ginsenoside Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: RH40=1:3(m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 186 Prescription 187 Prescription 188 Prescription 189 Prescription 190 Prescription 191 Ginsenosides 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ginsenoside, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 37 : Preparation of Ginsenoside Injection Solubilized with TPGS without Suffering Phenomenon (fixed TPGS: (F68+RH40)=1:1 (m/m), different amounts of propylene glycol are selected for polyols)

prescription:

the Prescription 192 Prescription 193 Prescription 194 Prescription 195 Prescription 196 Prescription 197 Ginsenosides 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ginsenoside, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 38: Preparation of Ginsenoside Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: (F68+RH40)=1:3(m/m), different amounts of glycerin are selected as polyols)

prescription:

the Prescription 198 Prescription 199 Prescription 200 Prescription 201 Prescription 202 Prescription 203 Ginsenosides 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ginsenoside, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 39: Preparation of Acyclovir Injection Solubilized with TPGS Alone

Prescription 204:

Acyclovir 60 mg

TPGS 600 mg

  Water for Injection                                          

            

            

30 mL

Process:

Weigh the prescribed amount of acyclovir and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all colorless transparent solutions.

Observation after sterilization: the preparation became turbid, and jelly-like substances were precipitated at the bottom of the bottle, indicating that TPGS did have obvious clouding phenomenon.

Example 40 : Preparation of Acyclovir Injection Solubilized with TPGS (Fixed TPGS: F68=1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 205 Prescription 206 Prescription 207 Prescription 208 Prescription 209 Prescription 210 Aciclovir 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of acyclovir and TPGS to form the oil phase; weigh the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 41: Preparation of Aciclovir Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: F68=1:3(m/m), Different Amounts of Glycerol for Polyols)

prescription:

the Prescription 211 Prescription 212 Prescription 213 Prescription 214 Prescription 215 Prescription 216 Aciclovir 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of acyclovir and TPGS to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS flashing.

Example 42 : Preparation of Acyclovir Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: RH40=1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 217 Prescription 218 Prescription 219 Prescription 220 Prescription 221 Prescription 222 Aciclovir 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of acyclovir, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 43: Preparation of Acyclovir Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: RH40=1:3(m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 223 Prescription 224 Prescription 225 Prescription 226 Prescription 227 Prescription 228 Aciclovir 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of acyclovir, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 44 : Preparation of Aciclovir Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: (F68+RH40)=1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 229 Prescription 230 Prescription 231 Prescription 232 Prescription 233 Prescription 234 Aciclovir 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of Acyclovir, TPGS, and RH40 to form the oil phase; weigh the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 45: Preparation of Aciclovir Injection Solubilized with TPGS without Sudden Phenomenon (Fixed TPGS: (F68+RH40)=1:3(m/m), Different Amounts of Glycerin for Polyols)

prescription:

the Prescription 235 Prescription 236 Prescription 237 Prescription 238 Prescription 239 Prescription 240 Aciclovir 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of Acyclovir, TPGS, and RH40 to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 46: Preparation of ribavirin injection solubilized with TPGS alone

Prescription 241:

                                    60 mg

TPGS 600 mg

  Water for Injection                                          

            

            

30 mL

Process:

Weigh the prescribed amount of ribavirin and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all colorless transparent solutions.

Observation after sterilization: the preparation became turbid, and jelly-like substances were precipitated at the bottom of the bottle, indicating that TPGS did have obvious clouding phenomenon.

Embodiment 47 : Preparation of Ribavirin Injection Solubilized with TPGS without Suffering (Fixed TPGS: F68=1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 242 Prescription 243 Prescription 244 Prescription 245 Prescription 246 Prescription 247 Ribavirin 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ribavirin and TPGS to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 48: Preparation of ribavirin injection solubilized with TPGS without dizziness (fixed TPGS: F68=1:3 (m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 248 Prescription 249 Prescription 250 Prescription 251 Prescription 252 Prescription 253 Ribavirin 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ribavirin and TPGS to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS flashing.

Embodiment 49 : Preparation of Ribavirin Injection Solubilized with TPGS (Fixed TPGS: RH40=1:1 (m/m), Polyol Selects Different Amounts of Propylene Glycol)

prescription:

the Prescription 254 Prescription 255 Prescription 256 Prescription 257 Prescription 258 Prescription 259 Ribavirin 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ribavirin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 50: Preparation of Ribavirin Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: RH40=1:3 (m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 260 Prescription 261 Prescription 262 Prescription 263 Prescription 264 Prescription 265 Ribavirin 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ribavirin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 51 : Preparation of Ribavirin Injection Solubilized with TPGS without Suffering (Fixed TPGS: (F68+RH40) = 1:1 (m/m), different amounts of propylene glycol are selected for polyols)

prescription:

the Prescription 266 Prescription 267 Prescription 268 Prescription 269 Prescription 270 Prescription 271 Ribavirin 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ribavirin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 52: Preparation of Ribavirin Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: (F68+RH40)=1:3(m/m), different amounts of glycerin were selected as polyols)

prescription:

the Prescription 272 Prescription 273 Prescription 274 Prescription 275 Prescription 276 Prescription 277 Ribavirin 60mg 60mg 60mg 60mg 60mg 60mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of ribavirin, TPGS, and RH40 to form the oil phase; weigh the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 53: Preparation of cucurbitacin injection solubilized with TPGS alone

Prescription 278:

                                   

TPGS 600 mg

  Water for Injection                                          

            

            

30 mL

Process:

Weigh the prescribed amount of cucurbitacin and TPGS to form the oil phase; measure the prescribed amount of water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the oil phase are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, aliquot, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparation was sterilized at 100°C for 30 minutes, and the other half was sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the obtained preparations are all colorless transparent solutions.

Observation after sterilization: the preparation became turbid, and jelly-like substances were precipitated at the bottom of the bottle, indicating that TPGS did have obvious clouding phenomenon.

Embodiment 54 : Preparation of cucurbitacin injection without turbidity phenomenon solubilized by TPGS (fixed TPGS: F68=1:1 (m/m), polyhydroxyl compound selects different amounts of propylene glycol)

prescription:

the Prescription 279 Prescription 280 Prescription 281 Prescription 282 Prescription 283 Prescription 284 Cucurbitacin 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cucurbitacin and TPGS to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 55: Preparation of Cucurbitacin Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: F68=1:3(m/m), different amounts of glycerol are selected for polyols)

prescription:

the Prescription 285 Prescription 286 Prescription 287 Prescription 288 Prescription 289 Prescription 290 Cucurbitacin 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cucurbitacin and TPGS to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

  Using the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results can eliminate the phenomenon of TPGS flashing.

Example 56 : Preparation of Cucurbitacin Injection Solubilized with TPGS (Fixed TPGS: RH40=1:1 (m/m), Polyols Select Different Amounts of Propylene Glycol)

prescription:

the Prescription 291 Prescription 292 Prescription 293 Prescription 294 Prescription 295 Prescription 296 Cucurbitacin 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 600mg 600mg 600mg 600mg 600mg 600mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cucurbitacin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 57: Preparation of Cucurbitacin Injection Solubilized with TPGS without Suffering Phenomenon (fixed TPGS: RH40=1:3(m/m), different amounts of glycerin are selected for polyols)

prescription:

the Prescription 297 Prescription 298 Prescription 299 Prescription 300 Prescription 301 Prescription 302 Cucurbitacin 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg RH40 1800mg 1800mg 1800mg 1800mg 1800mg 1800mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cucurbitacin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription are sterilized at 100°C for 30 minutes, and the other half are sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 58 : Preparation of Cucurbitacin Injection Solubilized with TPGS without Sudden Phenomenon (fixed TPGS: (F68+RH40)=1:1 (m/m), different amounts of propylene glycol are selected for polyols)

prescription:

the Prescription 303 Prescription 304 Prescription 305 Prescription 306 Prescription 307 Prescription 308 Cucurbitacin 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 300mg 300mg 300mg 300mg 300mg 300mg RH40 300mg 300mg 300mg 300mg 300mg 300mg Propylene Glycol 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cucurbitacin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, propylene glycol and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, glycerin, PEG200, PEG300, PEG400, PEG600 instead of propylene glycol to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Example 59: Preparation of Cucurbitacin Injection Solubilized with TPGS without Suffering Phenomenon (fixed TPGS: (F68+RH40)=1:3(m/m), different amounts of glycerin are selected as polyols)

prescription:

the Prescription 309 Prescription 310 Prescription 311 Prescription 312 Prescription 313 Prescription 314 Cucurbitacin 6mg 6mg 6mg 6mg 6mg 6mg TPGS 600mg 600mg 600mg 600mg 600mg 600mg F68 900mg 900mg 900mg 900mg 900mg 900mg RH40 900mg 900mg 900mg 900mg 900mg 900mg glycerin 1800mg 2400mg 3000mg 3600mg 4800mg 6000mg Water for Injection Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml Add to 30ml

Process:

Weigh the prescribed amount of cucurbitacin, TPGS, and RH40 to form the oil phase; measure the prescribed amount of F68, glycerin and water for injection as the water phase, and heat the two phases to 55°C respectively. After the substances in the two phases are completely dissolved, under the condition of magnetic stirring, slowly add the water phase into the oil phase, continue to stir for 20 min, dilute to 30 mL with water for injection, pass through a 0.22 μm microporous membrane, pack in aliquots, and fill with nitrogen , stoppered, sealed with an aluminum cap, half of the preparations of each prescription were sterilized at 100°C for 30 minutes, and the other half were sterilized at 121°C for 8 minutes.

Observe the state of the preparation before sterilization: the preparations obtained from the above six prescriptions are all colorless transparent solutions.

Immediately after sterilization, observe the state of the preparation: they are all colorless and transparent solutions, and there is no phenomenon of blurring in the preparation.

Use the same amount of xylitol, mannitol, glucose, trehalose, sucrose, propylene glycol, PEG200, PEG300, PEG400, PEG600 instead of glycerin to get consistent experimental results, which can eliminate the phenomenon of TPGS.

Claims (8)

1. can eliminate TPGS and rise the compositions of phenomenon covered with clouds, comprise insoluble drug, TPGS, poloxalkol and/or polyoxyethylene castor oil, polyol and water, wherein insoluble drug: TPGS: poloxalkol: the weight ratio of polyol is 0.001-2:1:0.5-5:2-20, surplus is water.

2. the compositions that can eliminate TPGS as claimed in claim 1 and rise phenomenon covered with clouds, is characterized in that: insoluble drug comprises ubiquinone ₁₀, fat-soluble A, D, E, K; Nimodipine, ginsenoside, Alprostadil, adenosine cyclophosphate, acyclovir, paclitaxel, Docetaxel, hydroxy camptothecin, ribavirin, cucurbitacin, at interior poorly water-soluble, can be used the medicine of TPGS increase-volume.

3. the TPGS of elimination as claimed in claim 1 plays the compositions of phenomenon covered with clouds, it is characterized in that: the poloxalkol in compositions is EOn-POm-EOn.

4. polyoxyethylene (hydrogenation) Oleum Ricini in compositions as claimed in claim 1, is characterized in that: can be a kind of or several mixture in the poly-hydrogen-oxygen ester 35 of polyoxyl 40 hydrogenated castor oil RH40, Oleum Ricini, the poly-hydrogen-oxygen ester 35 of Oleum Ricini.

5. the TPGS of elimination as claimed in claim 1 plays the compositions of phenomenon covered with clouds, it is characterized in that: when compositions is made up of insoluble drug, TPGS, polyoxyethylene castor oil, polyol and water, wherein insoluble drug: TPGS: polyoxyethylene castor oil: the weight ratio of polyol is 0.001-2:1:0.5-5:2-20, surplus is water.

6. the TPGS of elimination as claimed in claim 1 plays the compositions of phenomenon covered with clouds, it is characterized in that: polyol is a kind of or several mixture in glucose, xylose, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, sorbitol, maltol, propylene glycol, glycerol, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000 etc.

7. described eliminated TPGS plays the compositions of phenomenon covered with clouds as claimed in claim 1, it is characterized in that: water is the one in purified water, distilled water, water for injection, sterilizing purified water, sterilized water for injection.

8. described eliminated TPGS plays the compositions of phenomenon covered with clouds as claimed in claim 1, it is characterized in that: the ubiquinone that takes recipe quantity ₁₀, TPGS forms oil phase; Measure the water for injection of recipe quantity as water, be biphasely heated to respectively 55 ℃, after material in oil phase dissolves completely, under the condition of magnetic agitation, water is slowly added in oil phase, continue to stir 20 min, water for injection is diluted to 30 mL, crosses 0.22 μ m microporous filter membrane, subpackage, inflated with nitrogen, jump a queue, sealing, half preparation is with 100 ℃, the condition sterilizing of 30 min, second half,, with 121 ℃, 8 min sterilizings, to obtain final product.