CN113329736A

CN113329736A - Self-emulsifying oral preparation of terpene medicinal composition, preparation method and application

Info

Publication number: CN113329736A
Application number: CN201980087982.3A
Authority: CN
Inventors: 沈芳玲; 赵家欣; 聂红梅; 韩悦; 石江林
Original assignee: Beijing Grand Johamu Pharmaceutical Co Ltd
Current assignee: Beijing Grand Johamu Pharmaceutical Co Ltd
Priority date: 2019-01-15
Filing date: 2019-11-19
Publication date: 2021-08-31
Anticipated expiration: 2039-11-19
Also published as: CN113329736B; WO2020147416A1; CN109528649A; CN109528649B

Abstract

A terpene pharmaceutical composition self-emulsifying oral preparation, its preparation method and application, the said self-emulsifying oral preparation includes the pharmaceutical composition of eucalyptol, limonene and alpha-pinene of the specific proportion and emulsifier, optional grease and auxiliary emulsifier, cooperate with each other among every component, make the terpene pharmaceutical composition self-emulsifying liquid medicine nature made stable, homogeneous, have improved the quality stability of the terpene pharmaceutical composition self-emulsifying oral preparation, has guaranteed the therapeutic effect of the medicament, suitable for clinical large-area popularization and use.

Description

Self-emulsifying oral preparation of terpene medicinal composition, preparation method and application

PRIORITY INFORMATION

This application requests priority and benefit of a patent application having patent application number 201910036486.7 filed on.1, 15, 2019 with the chinese national intellectual property office and is incorporated herein by reference in its entirety.

Technical Field

The invention relates to the technical field of medicinal preparations, and relates to a self-emulsifying oral preparation of a terpene medicinal composition, a preparation method and application thereof.

Background

The pharmaceutical composition containing eucalyptol, limonene and alpha-pinene can be used for relieving cough, diminishing inflammation, eliminating phlegm and promoting discharge of contrast medium for respiratory disease patients, and can be used as an atomizing inhalant for improving the function damage of mucociliary clearance system caused by rhinitis and nasosinusitis, for example, the prior art discloses a pharmaceutical composition fat emulsion injection containing eucalyptol, limonene and alpha-pinene and a preparation method thereof, wherein the injection comprises, by weight, 0.0128-0.032% of eucalyptol, 0.0084-0.0210% of limonene, 0.0028-0.0070% of alpha-pinene, 10-30% of soybean oil for injection, 1.0-1.5% of egg yolk lecithin for injection or 0.8-1.5% of soybean phospholipid for injection, 2.0-2.5% of glycerol for injection and 100mL of water for injection, and the injection has various effects of diluting sputum, promoting acceleration of movement of trachea and bronchus cilium, resisting inflammation and the like, the injection is suitable for patients with stomach diseases and diabetes mellitus, but as the injection, the injection is expensive in market price, is generally only suitable for clinical emergency treatment medicines and is not suitable for consolidation treatment medicines in the recovery period, and patients are inconvenient to use at home. Therefore, there is a need to develop an oral formulation of a pharmaceutical composition comprising eucalyptol, limonene and alpha-pinene.

Self-emulsifying drug delivery systems (SEDDS) are homogeneous, clear, homogeneous solutions composed of an oil solution and a surfactant, and sometimes including a cosolvent. The system spontaneously forms an oil-in-water emulsion in the aqueous phase of gastric juice after oral administration due to gastric motility and the presence of emulsifiers. Compared with emulsion, SEDDS belongs to a thermodynamic stable system, and has the advantages of simple process, stable property and convenient storage. In addition, the self-emulsifying preparation is convenient to administer, can be prepared into various administration forms such as capsules, tablets, pellets and the like, is accurate in dosage and convenient to take, is suitable for large-scale production, and has great development prospect and application value.

However, eucalyptol, limonene and alpha-pinene are three different substances with certain differences in properties, self-emulsifying liquid medicine of terpene pharmaceutical compositions containing eucalyptol, limonene, alpha-pinene and the like prepared by using a surfactant and/or a cosolvent in the prior art is unstable and easy to generate layering phenomenon, and a large amount of non-emulsified oil drops of the pharmaceutical compositions exist on the surface when the self-emulsifying liquid medicine is dispersed in water, so that uniform liquid medicine is difficult to form, the quality of the self-emulsifying preparation of the pharmaceutical composition is unstable, and the large-area popularization and application of the self-emulsifying liquid medicine are greatly limited.

Disclosure of Invention

Therefore, the technical problem to be solved by the invention is to overcome the defect of unstable preparation quality of the oral preparation of the pharmaceutical composition containing eucalyptol, limonene and alpha-pinene prepared by the existing method, thereby providing a self-emulsifying oral preparation of terpene pharmaceutical composition. Meanwhile, the invention also provides a preparation method and application of the self-emulsifying oral preparation of the terpene pharmaceutical composition.

In order to solve the technical problems, the invention provides a self-emulsifying oral preparation. According to an embodiment of the invention, the self-emulsifying oral formulation comprises: active ingredients including eucalyptol, lemon, and alpha-pinene; and a pharmaceutical carrier. The self-emulsifying oral preparation provided by the embodiment of the invention has the advantages of high stability, narrow particle size distribution range, fast drug absorption, high oral bioavailability and small gastrointestinal adverse reaction.

According to an embodiment of the present invention, the self-emulsifying oral preparation may further comprise at least one of the following additional technical features:

according to an embodiment of the invention, the self-emulsifying oral formulation comprises: 40-65 parts by weight of the eucalyptol; 25 to 45 parts by weight of the limonene; and 5-20 parts by weight of the alpha-pinene.

According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (1-15): 10.

According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (1-6): 10.

According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (1-5): 10.

According to the embodiment of the invention, the weight ratio of the active ingredient to the drug carrier is (5-6): 10. The inventor finds that the weight ratio of the active ingredient to the drug carrier is (5-6): 10, the stability of the self-emulsifying oral preparation is further improved, the dispersed particle size in water is further reduced, the drug absorption is better, and the gastrointestinal reaction is further reduced.

According to an embodiment of the invention, the weight ratio of the active ingredient to the pharmaceutical carrier is 5.4: 10.

According to an embodiment of the invention, the drug carrier comprises: an emulsifier; optionally a grease; and optionally a co-emulsifier.

According to an embodiment of the present invention, the emulsifier comprises at least one selected from the group consisting of tween, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, phospholipid, caprylic capric acid macrogol glyceride.

According to an embodiment of the invention, the phospholipids comprise soy phospholipids.

According to an embodiment of the present invention, the oil or fat includes at least one selected from the group consisting of soybean oil, medium chain triglyceride, ethyl oleate, corn oil, and olive oil.

According to an embodiment of the present invention, the co-emulsifier comprises at least one selected from the group consisting of ethanol, 1, 2-propanediol, glycerol, polyethylene glycol, diethylene glycol monoethyl ether.

According to an embodiment of the invention, the drug carrier comprises: 10 to 50 parts by weight of the oil; 40-80 parts by weight of the emulsifier; and 5-30 parts by weight of the co-emulsifier.

According to an embodiment of the invention, the drug carrier comprises: 10 to 35 parts by weight of the oil; 50-70 of the emulsifier; and 10-25 parts by weight of the co-emulsifier.

According to an embodiment of the invention, the drug carrier comprises: 25 to 35 parts by weight of the medium chain triglyceride; 50-65 parts by weight of the caprylic/capric polyethylene glycol glyceride; and 10-15 parts by weight of diethylene glycol monoethyl ether.

According to an embodiment of the invention, the pharmaceutical carrier comprises: 0 to 5 parts by weight of the oil; 0-5 parts by weight of the co-emulsifier; 90-100 parts by weight of the emulsifier. The inventor finds that the dosage of the hydrophilic coemulsifier of the drug carrier is greatly reduced in the dosage range of the components, so that the layering phenomenon of the concentrated solution is greatly reduced, and meanwhile, the inventor also finds that the dispersion particle size of the concentrated solution in water is greatly reduced, so that the drug carrier is more favorable for promoting drug absorption and reducing the adverse reaction of gastrointestinal tracts; moreover, the dosage of the grease is greatly reduced, only the oily active ingredients provide oily ingredients of the preparation, the use of an oil phase is reduced on the basis of ensuring the self-emulsifying effect, the dosage of auxiliary materials is reduced, and the preparation is beneficial to being pressed into a smaller preparation form.

According to an embodiment of the invention, the emulsifier consists of at least two emulsifiers.

According to the embodiment of the invention, the emulsifier consists of a first emulsifier and a second emulsifier, and the mass fraction of the first emulsifier is 20-80% and the mass fraction of the second emulsifier is 10-70% based on the total mass of the self-emulsifying oral preparation.

According to an embodiment of the invention, the pharmaceutical carrier is constituted by the emulsifier.

According to an embodiment of the invention, the self-emulsifying oral formulation is in the form of a hard capsule, a soft capsule or a tablet.

According to an embodiment of the invention, the self-emulsifying oral formulation comprises: 18.2g of eucalyptol, 16.4g of limonene, 1.8g of alpha-pinene, 181.8g of soybean oil, 145.4g of tween 80 and 36.4g of propylene glycol; or

73.3g eucalyptol, 33.3g limonene, 26.6g alpha-pinene, 26.7g medium chain triglyceride, 213.4g caprylic capric polyethylene glycol glyceride, 26.7g diethylene glycol monoethyl ether; or

14.6g eucalyptol, 16.4g limonene, 5.4g alpha-pinene, 90.9g medium chain triglyceride, 236.6g caprylic capric polyethylene glycol glyceride, 36.4g diethylene glycol monoethyl ether; or

86.6g of eucalyptol, 40.0g of limonene, 6.6g of alpha-pinene, 93.4g of medium chain triglyceride, 133.4g of caprylic capric polyethylene glycol glyceride, 40g of diethylene glycol monoethyl ether; or

53.3g eucalyptol, 53.3g limonene, 26.6g alpha-pinene, 26.7g ethyl oleate, 160.1g polyoxyethylene castor oil, 80.0g diethylene glycol monoethyl ether; or

78.0g eucalyptol, 36.0g limonene, 6.0g alpha-pinene, 126g corn oil, 140g polyoxyethylene hydrogenated castor oil, 14.0g propylene glycol; or

42.7g of eucalyptol, 28.0g of limonene, 9.3g of alpha-pinene, 80g of soybean oil, 180g of tween 80 and 60g of PEG-400; or

69.3g of eucalyptol, 45.5g of limonene, 15.2g of alpha-pinene, 40g of corn oil, 170g of polyoxyethylene castor oil and 60g of propylene glycol; or

70.0g of eucalyptol, 45.5g of limonene, 14.5g of alpha-pinene, 40g of soybean oil, 180g of polyoxyethylene hydrogenated castor oil and 50g of propylene glycol; or

70.0g of eucalyptol, 45.5g of limonene, 14.5g of alpha-pinene, 50g of ethyl oleate, 160g of caprylic/capric polyethylene glycol glyceride and 60g of diethylene glycol monoethyl ether; or

69.3g of eucalyptol, 45.5g of limonene, 15.2g of alpha-pinene, 40g of soybean oil, 170g of Tween 80 and 60g of propylene glycol; or

75g of eucalyptol, 50g of limonene, 16g of alpha-pinene, 79g of Tween 80, and 180g of caprylic capric acid polyethylene glycol glyceride; or

75g of eucalyptol, 50g of limonene, 16g of alpha-pinene, 165g of caprylic/capric polyethylene glycol glyceride and 94g of polyoxyethylene castor oil.

In a second aspect of the invention, the invention provides a process for preparing the self-emulsifying oral formulation as hereinbefore described. According to an embodiment of the invention, the method comprises: mixing said active ingredient with said pharmaceutical carrier so as to obtain said self-emulsifying oral formulation.

According to an embodiment of the present invention, the method may further include at least one of the following additional technical features:

according to an embodiment of the present invention, further comprising encapsulating the mixture comprising the active ingredient and the pharmaceutical carrier so as to obtain a formulation.

According to an embodiment of the invention, the formulation is a soft capsule, a hard capsule or a tablet.

According to an embodiment of the invention, mixing the active ingredient with the pharmaceutical carrier further comprises: subjecting the active ingredient and optionally the fat to a first mixing treatment so as to obtain an oily phase mixture; and carrying out second mixing treatment on the oil-phase mixture, the emulsifier and the optional coemulsifier.

According to an embodiment of the present invention, the first mixing process and the second mixing process are each independently performed under the following conditions: the temperature is 15-30 ℃; the stirring speed is as follows: 30-50 rpm; and/or the mixing time is 1-2 hours.

According to an embodiment of the invention, the medicament is for the treatment or prevention of a respiratory disease.

According to an embodiment of the invention, the respiratory disease comprises: acute sinusitis, chronic sinusitis, sinusitis operation inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary disease, pulmonary fungal infection, pulmonary tuberculosis, and silicosis.

In a third aspect of the invention, a method of treating or preventing a respiratory disorder is presented. According to an embodiment of the invention, the method comprises administering the self-emulsifying oral formulation as described above to a patient with a respiratory disorder. According to the method provided by the embodiment of the invention, the self-emulsifying oral preparation has the advantages of faster absorption, higher oral bioavailability, weaker gastrointestinal reaction of patients and better treatment effect.

The technical scheme of the invention has the following advantages:

1. the terpene medicinal composition self-emulsifying oral preparation provided by the invention comprises a medicinal composition of eucalyptol, limonene and alpha-pinene in a specific proportion, grease, an emulsifier and an auxiliary emulsifier, and all the components are matched with each other, so that the prepared terpene medicinal composition self-emulsifying liquid medicine is stable and uniform in property, the quality stability of the terpene medicinal composition self-emulsifying oral preparation is improved, the treatment effect of the medicine is ensured, and the terpene medicinal composition self-emulsifying oral preparation is suitable for large-area clinical popularization and use.

2. The terpene medicinal composition self-emulsifying oral preparation provided by the invention further limits the types and contents of the emulsifying agent and the co-emulsifying agent, improves the uniformity of the self-emulsifying liquid medicine of the terpene medicinal composition, and is beneficial to improving the quality of the self-emulsifying oral preparation.

3. The terpene pharmaceutical composition self-emulsifying oral preparation provided by the invention can spontaneously form an oil-in-water microemulsion in a water phase of gastric juice after oral administration under the action of gastric peristalsis and an emulsifier and an auxiliary emulsifier, effectively cover the taste of eucalyptol, limonene and alpha-pinene, reduce the stimulation of the medicine to the gastrointestinal tract, avoid the occurrence of adverse reactions such as nausea, vomiting, diarrhea and the like, and is suitable for patients with a gastric disease history.

4. The terpene medicine composition self-emulsifying oral preparation provided by the invention enters gastric juice through oral administration, and contacts with water in the gastric juice to form medicine-carrying microemulsion, the medicine composition exists in the tiny oil drops and is rapidly distributed in the whole stomach, the dissolution of the water-insoluble medicine is greatly improved by depending on the huge specific surface area of the tiny oil drops, so that the medicine can more easily pass through a hydration layer of the gastrointestinal wall, the permeability of epithelial cells of the medicine is increased, the absorption of the medicine is promoted, and the problem that the terpene medicine is difficult to absorb in a human body is effectively solved.

5. The terpene pharmaceutical composition self-emulsifying oral preparation provided by the invention comprises eucalyptol, limonene and alpha-pinene which are all natural products, and has the advantages of wide sources, simple process, low cost, definite chemical structure and composition, low toxicity and high safety.

6. The preparation method of the self-emulsifying oral preparation of the terpene pharmaceutical composition provided by the invention has the advantages of simple process, low cost, good stability and controllable quality, can be used for preparing self-emulsifying liquid medicine into oral dosage forms such as soft capsules, hard capsules, tablets, granules, dropping pills or pellets and the like, and is suitable for large-scale batch production.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

FIG. 1 is a pseudo-ternary phase diagram of mixed oil phase Tween 80-PEG-400 according to the embodiment of the present invention;

FIG. 2 is a pseudo-ternary phase diagram of mixed oil phase Tween 80-Transcutol according to the embodiment of the invention;

FIG. 3 is a pseudo-ternary phase diagram of a mixed oil phase-Labrasol-PEG 400 according to an embodiment of the present invention;

FIG. 4 is a pseudo-ternary phase diagram of a mixed oil phase-Labrasol-Transcutol according to an embodiment of the present invention;

FIG. 5 is a pseudo ternary phase diagram of the oil-free co-emulsifier-eucalyptol and pinene oil-emulsifier 1-emulsifier 2 according to an embodiment of the present invention;

fig. 6 is a representative particle size distribution diagram of a self-emulsifying drug solution in accordance with an embodiment of the present invention.

Detailed Description

Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.

It should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Further, in the description of the present invention, "a plurality" means two or more unless otherwise specified.

The invention mainly researches the prescription composition and the preparation process of the self-emulsifying preparation from three parts of preliminary prescription screening, pseudo-ternary phase diagram drawing and orthogonal test to determine the optimal prescription of the self-emulsifying concentrated solution of the pharmaceutical composition.

(1) Preliminary screening of prescriptions

The formula proportion of the fixed self-emulsifying concentrated solution is unchanged, different grease, emulsifiers and co-emulsifiers are respectively used for preparing the self-emulsifying concentrated solution, and proper grease, emulsifiers and co-emulsifiers are screened according to the self-emulsifying effect.

The formulation for designing the self-emulsifying formulation was:

wherein the screened oil comprises soybean oil, corn oil, medium chain triglyceride, and ethyl oleate; the screened emulsifier comprises Tween 80, polyoxyethylene castor oil (EL-35), polyoxyethylene hydrogenated castor oil (RH-40), caprylic capric acid polyethylene glycol glyceride (Labrasol); the screened coemulsifier comprises propylene glycol, glycerol, diethylene glycol monoethyl ether (Transcutol) and PEG-400.

The fixed oil was soybean oil, and the results of screening the types of emulsifiers and co-emulsifiers are shown in Table 1.

TABLE 1 preliminary screening results for emulsifiers, coemulsifiers

The fixed emulsifier is tween 80, the co-emulsifier is propylene glycol, and the results of screening the grease types are shown in table 2.

TABLE 2 results of screening of oil and fat species

By combining the test results, the common soybean oil is selected as the grease, the Tween 80 and the caprylic/capric polyethylene glycol glyceride with good self-emulsifying effect are used as the emulsifying agents, and the PEG-400 and the diethylene glycol monoethyl ether are used as the auxiliary emulsifying agents for subsequent tests.

In addition, the inventor unexpectedly discovers in experiments that if the dosage of the grease and the auxiliary emulsifier is reduced as much as possible, and the composite emulsifier is adopted, the emulsification rate is greatly improved, and the particle size of emulsion drops is greatly reduced.

Table 3 presents the appearance of the concentrate, the rate of emulsification and the droplet size data after the inventors have attempted to reduce the oil or co-emulsifier during the course of the experiment.

Table 3:

(2) drawing of pseudo ternary phase diagram

And drawing a pseudo ternary phase diagram of each combined oil phase-emulsifier-co-emulsifier, and determining an effective self-emulsifying area formed by each prescription. The results are shown in FIGS. 1-4 (marked with effective self-emulsifying region), and the mass ratio of the effective self-emulsifying region formed by taking the pseudo-ternary phase diagram of oil phase-Tween 80-PEG-400 (shown in FIG. 1) is oil phase 0.1-0.4, Tween 800.4-0.9, and PEG-4000.1-0.6. The subsequent test is carried out by selecting the prescription proportion with higher oil phase content.

In addition, the inventor draws a pseudo ternary phase diagram by using the grease-free auxiliary emulsifier-eucalyptol and pinene oil-emulsifier 1-emulsifier 2, determines effective self-emulsifying areas of each formula composition, and the result is shown in fig. 5. As can be seen from the figure, in the range of the effective self-emulsifying region, the proportion of the eucalyptus and pinene oil is 10-60%, the proportion of the auxiliary material emulsifier 1 is 20-80%, and the proportion of the emulsifier 2 is 10-70%. Therefore, the ratio of the drug to the carrier is 1: 9-6: 4, namely the drug: the carrier (1.1-15) is 10.

(3) Quadrature test

And designing a proper factor level table and an orthogonal test table, and screening an optimal formula of the self-emulsifying concentrated solution through the self-emulsifying rate and the emulsion drop particle size.

The factor levels for designing the orthogonal test are shown in table 4, using the pharmaceutical composition and soybean oil as oil phase, tween 80 as emulsifier, and PEG-400 as co-emulsifier.

TABLE 4 orthogonal test factor horizon

The test results are shown in Table 5.

TABLE 5 results of orthogonal tests

By an intuitive analysis method, the optimal formula is obtained to be 0.30g of oil phase, 800.50 g of Tween and 4000.15 g of PEG-E. The formula is repeated for three times, the dispersion rate of the prepared self-emulsifying concentrated solution in water is 20-40 s, and the particle size of emulsion drops is 150-180 nm.

The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.

The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.

In the following examples, eucalyptol, limonene and alpha-pinene may be prepared as follows: rectifying eucalyptus oil (crude oil) prepared from eucalyptus globulus labill of eucalyptus of Myrtaceae to obtain eucalyptol with content of 80-85%; squeezing pericarpium Citri Limoniae of Citrus of Rutaceae, distilling with steam to obtain lemon oil (crude oil), and rectifying to obtain limonene with content of 93% or more; steam distilling and refining oleoresin exuded from Pinus massoniana of Pinaceae to obtain alpha-pinene with content of more than 90%.

EXAMPLE 1 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation method comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and soybean oil in the prescription amount, stirring for 1 hour at the rotation speed of 50rpm at 15 ℃, and uniformly mixing to obtain an oil phase;

(2) adding Tween 80 and propylene glycol into the oil phase, stirring at 15 deg.C and 50rpm for 1 hr, and mixing to obtain uniform self-emulsifying medicinal liquid;

(3) according to the weight ratio of 1: 0.5: 1.1 preparing capsule shell by weighing gelatin, glycerol and water;

(4) and (3) pressing the self-emulsifying liquid medicine obtained in the step (2) and the capsule skin obtained in the step (3) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the terpene medicinal composition self-emulsifying soft capsule.

EXAMPLE 2 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation method comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and medium-chain triglyceride in the prescription amount, stirring for 2 hours at the rotation speed of 30rpm at the temperature of 30 ℃, and uniformly mixing to obtain an oil phase;

(2) adding Labrasol and Transcutol in the prescription amount into an oil phase, stirring at 30 ℃ and 30rpm for 2 hours, and uniformly mixing to form a uniform self-emulsifying liquid medicine;

(3) preparing capsule shells by weighing gelatin, glycerol and water according to the weight ratio of 1:0.45: 1.1;

EXAMPLE 3 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation method is the same as example 2.

EXAMPLE 4 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation method is the same as example 2.

EXAMPLE 5 preparation of terpene pharmaceutical compositions self-emulsifying hard capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation method comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and ethyl oleate in the formula amount, stirring for 2 hours at 20 ℃, and uniformly mixing to obtain an oil phase;

(2) adding the polyoxyethylene castor oil and the diethylene glycol monoethyl ether in the formula amount into the oil phase, and stirring for 2 hours at 20 ℃ to uniformly mix to form a uniform self-emulsifying liquid medicine;

(3) and (3) dripping the self-emulsifying liquid medicine obtained in the step (2) into micropowder silica gel under the condition of stirring, adding magnesium stearate, and subpackaging into hard capsules to obtain the terpene medicinal composition self-emulsifying hard capsules.

EXAMPLE 6 preparation of terpene pharmaceutical compositions self-emulsifying tablet

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation method comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and corn oil in the prescription amount, stirring for 2 hours at 20 ℃, and uniformly mixing to obtain an oil phase;

(2) adding the polyoxyethylene hydrogenated castor oil and propylene glycol in the oil phase according to the prescription amount, and stirring for 2 hours at 20 ℃ to uniformly mix to form uniform self-emulsifying liquid medicine;

(3) dripping the self-emulsifying liquid medicine obtained in the step (2) into superfine silica gel powder under the stirring condition, adding auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate and the like, and preparing the terpene medicinal composition self-emulsifying tablet by adopting a conventional direct tabletting method.

EXAMPLE 7 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation process comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and soybean oil in the prescription amount, stirring for 1 hour at 20 ℃, and uniformly mixing to obtain an oil phase;

(2) adding Tween 80 and PEG-400 into the oil phase, stirring at 20 deg.C for 2 hr, and mixing to obtain self-emulsifying concentrated solution;

(3) preparing capsule shells by weighing gelatin, glycerol and water according to the weight ratio of 1: 0.3-0.65: 0.9-1.3;

(4) and (3) preparing the self-emulsifying concentrated solution obtained in the step (2) and the capsule shell obtained in the step (3) into soft capsules in a conventional manner.

EXAMPLE 8 preparation of terpene pharmaceutical compositions self-emulsifying Soft capsules

The prescription of the self-emulsifying liquid medicine is as follows:

the preparation process comprises the following steps:

(2) adding the polyoxyethylene castor oil and the propylene glycol into the oil phase according to the prescription amount, and stirring for 2 hours at 20 ℃ to uniformly mix to form self-emulsifying concentrated solution;

(3) preparing capsule shells by weighing gelatin, glycerol and water according to the weight ratio of 1: 0.4-0.6: 1.0-1.3;

EXAMPLE 9 preparation of self-emulsifying Soft capsules of pharmaceutical composition

The prescription of the contents:

the preparation process is the same as example 6.

EXAMPLE 10 preparation of self-emulsifying Soft capsules of pharmaceutical composition

The prescription of the contents:

the preparation process is the same as example 6.

EXAMPLE 11 preparation of pharmaceutical composition self-emulsifying hard capsules

The prescription of the contents:

the preparation process comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and soybean oil in the prescription amount, stirring for 2 hours at 20 ℃, and uniformly mixing to obtain an oil phase;

(2) adding the Tween 80 and propylene glycol into the oil phase according to the prescription amount, and uniformly mixing the mixture for 2 hours at the temperature of 20 ℃ to form a self-emulsifying concentrated solution;

(3) and (3) dripping the self-emulsifying concentrated solution obtained in the step (2) into a proper amount of superfine silica gel powder under stirring, adding magnesium stearate, and subpackaging into hard capsules.

EXAMPLE 12 preparation of pharmaceutical composition self-emulsifying tablet

The prescription of the concentrated solution is as follows:

the preparation process comprises the following steps:

(3) and (3) dripping the self-emulsifying concentrated solution obtained in the step (2) into a proper amount of superfine silica gel powder under stirring, adding auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate and the like, and preparing the self-emulsifying concentrated solution from the emulsifying tablets by adopting a conventional direct tabletting method.

Example 13: preparation of self-emulsifying soft capsule of medicinal composition

The prescription of the contents:

the preparation process comprises the following steps:

(1) taking eucalyptol, limonene and alpha-pinene in the prescription amount, stirring for 1 hour at 20 ℃, and uniformly mixing to obtain an oil phase;

(2) adding Tween 80 and polyethylene glycol caprylic capric acid into the oil phase, stirring at 20 deg.C for 2 hr, and mixing to obtain self-emulsifying concentrated solution;

EXAMPLE 14 preparation of self-emulsifying Soft Capsule for pharmaceutical composition

The prescription of the contents:

the preparation process comprises the following steps:

(2) adding prescription dose of caprylic/capric polyethylene glycol glyceride and polyoxyethylene castor oil into an oil phase, and stirring for 2 hours at 20 ℃ to uniformly mix to form a self-emulsifying concentrated solution;

The inventors have found that the removal of hydrophilic co-emulsifiers from the self-emulsifying concentrates of examples 13 and 14 reduces the stratification of the concentrates, facilitates the mixing of large amounts of drug, and improves the uniformity of drug content.

Comparative example 1 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule Using existing self-emulsifying formulation Process

According to the disclosed self-emulsifying preparation formula, the formula of the self-emulsifying medicinal liquid of the terpene medicinal composition is designed as follows:

the preparation method is disclosed as follows:

(1) taking eucalyptol, limonene and alpha-pinene in the prescription amount, adding ethyl oleate, and uniformly mixing to obtain an oil phase;

(2) mixing the Tween 80 and PEG-400 according to the prescription amount, and uniformly mixing by using a magnetic stirrer to obtain an emulsified phase;

(3) mixing the oil phase and the emulsified phase, and uniformly mixing in a stirring, vibrating, ultrasonic or vortex mode to form self-emulsified liquid medicine;

(4) according to the weight ratio of 1:0.45:1.1 preparing capsule shell by weighing gelatin, glycerol and water;

(5) and (4) pressing the self-emulsifying liquid medicine obtained in the step (3) and the capsule skin obtained in the step (4) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the self-emulsifying soft capsule.

Comparative example 2 preparation of terpene-based pharmaceutical composition self-emulsifying Soft Capsule Using the existing formulation of self-emulsifying preparation and the preparation method of the present invention

the preparation method comprises the following steps:

(1) taking eucalyptol, limonene, alpha-pinene and ethyl oleate in the formula amount, stirring at the rotation speed of 50rpm for 1 hour at 15 ℃, and uniformly mixing to obtain an oil phase;

(2) adding Tween 80 and PEG-400 into the oil phase, stirring at 15 deg.C and 50rpm for 1 hr to obtain emulsified medicinal liquid;

(4) and (3) pressing the self-emulsifying liquid medicine obtained in the step (2) and the capsule skin obtained in the step (3) on a soft capsule machine in a conventional mode, and setting in a setting machine to prepare the self-emulsifying soft capsule.

EXAMPLE 15 Property observations of different self-emulsifying formulations

The oil phase, the emulsifier and the co-emulsifier are respectively used as one phase, the components are fully mixed according to different proportions, the mixture is kept stand for 2 hours, and whether a uniform, transparent and non-layered solution is formed or not is observed visually. 0.5mL of the formulation that formed a uniform, clear solution was removed and added dropwise to 50mL of purified water at 37 ℃ with stirring at 50rpm to see if a clear, clear emulsion was formed.

The results show that: 1. the self-emulsifying liquid medicines in the comparative examples 1 and 2 are layered after standing, the self-emulsifying liquid medicine layering phenomenon of the comparative example 1 is more serious, and the self-emulsifying liquid medicines of the examples 1 to 11 of the invention are not layered after standing; 2. the self-emulsifying liquid medicines in comparative examples 1 and 2 cannot be rapidly dispersed into uniform emulsion in water, a large number of oil droplets float on the surface of water after dispersion, and effective self-emulsification cannot be realized, while the self-emulsifying liquid medicines in examples 1 to 11 of the present invention can be rapidly and uniformly dispersed in water, and the formed emulsion droplets have small particle size and uniform particle size distribution.

It is thus understood that the self-emulsifying preparation technology disclosed in the prior art is not easily applied directly to the terpene-based pharmaceutical composition of the present invention, and that the self-emulsifying preparation of a terpene-based pharmaceutical composition prepared according to the prior art cannot achieve a good self-emulsifying effect.

Example 16 particle size measurement of self-emulsifying Dispersion

0.5mL of the self-emulsifying drug solution of examples 1 to 11 was dispersed in 50mL of purified water at 37 ℃, and the particle size of the emulsion droplets was measured by a laser particle sizer for 2mL of the dispersion, and the results are shown in Table 6, and a typical particle size distribution chart of the self-emulsifying drug solution of example 1 is shown in FIG. 6. The self-emulsified concentrated solution prepared by the formulation in example 1 can be rapidly dispersed into nano-scale emulsion with uniform particle size in water, the dispersion rate is 20-40 s, the average particle size is (161.4 +/-17.6) nm, and the polydispersity is 0.278 +/-0.101.

Table 6: examples 1 to 14 self-emulsifying agent Dispersion Rate and emulsion droplet particle diameter

Examples	Rate of dispersion(s)	Particle size (nm)	Polydisperse coefficient (PDI)
Example 1	30.7	142.5	0.257
Example 2	19.2	171.2	0.193
Example 3	13.5	161.9	0.219

Example 4	13.2	177.6	0.195
Example 5	29.6	164.6	0.274
Example 6	21.5	170.1	0.298
Example 7	18.9	160.6	0.230
Example 8	30.6	175.7	0.309
Example 9	44.9	161.7	0.265
Example 10	49.6	189.2	0.202
Example 11	56.5	157.8	0.257
Example 12	56.5	157.8	0.257
Example 13	64.3	106.25	0.271
Example 14	53.1	42.28	0.168

As can be seen from Table 6 and FIG. 6, the self-emulsifying agents of examples 1 to 14 of the present invention can be rapidly dispersed in water to form nano-emulsions having uniform particle sizes, a dispersion rate of 10 to 65 seconds, an average particle size of 40 to 190nm, and a polydispersity of 0.150 to 0.32. The self-emulsifying liquid medicine of the embodiments 13 and 14 has the advantages that the dispersion particle size in water is obviously reduced, the average particle size of the embodiments 1 to 12 is 140 to 190nm, the particle size of the embodiment 13 is only 100 to 110nm, the particle size of the embodiment 14 is 40 to 50nm, the embodiments 13 and 14 have obviously smaller particle sizes, the medicine absorption is promoted, the adverse reaction of gastrointestinal tracts is reduced, an oil phase is not used, the using amount of auxiliary materials is effectively reduced, the cost is saved, and the self-emulsifying liquid medicine can be pressed into smaller soft capsules and is convenient to swallow.

The self-emulsifying liquid medicine prepared by the invention can rapidly disperse the eucalyptol, limonene and alpha-pinene medicinal composition into the nano-emulsion, has smaller particle size, is favorable for accelerating medicament absorption and simultaneously reduces adverse reaction of gastrointestinal tracts.

Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an illustrative embodiment," "an example," "a specific example," or "some examples" or the like mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

Claims

A self-emulsifying oral formulation comprising:

active ingredients including eucalyptol, lemon, and alpha-pinene; and

a drug carrier.
The self-emulsifying oral formulation of claim 1, wherein the self-emulsifying oral formulation comprises:

40-65 parts by weight of the eucalyptol;

25 to 45 parts by weight of the limonene; and

5-20 parts by weight of the alpha-pinene.
The self-emulsifying oral formulation according to any one of claims 1 to 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is (1 to 15): 10.
The self-emulsifying oral formulation according to any one of claims 1 to 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is (1 to 5): 10.
The self-emulsifying oral formulation according to any one of claims 1 to 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is (5 to 6): 10.
The self-emulsifying oral formulation according to any one of claims 1 to 2, wherein the weight ratio of the active ingredient to the pharmaceutical carrier is 5.4: 10.
The self-emulsifying oral formulation according to any one of claims 1 to 2, wherein the pharmaceutical carrier comprises:

an emulsifier;

optionally a grease; and

optionally a co-emulsifier.
The self-emulsifying oral formulation according to claim 7, wherein the emulsifier comprises at least one selected from the group consisting of tween, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, phospholipid, caprylic capric acid polyethylene glycol glyceride.
The self-emulsifying oral formulation of claim 8, wherein the phospholipid comprises a soybean phospholipid.
The self-emulsifying oral formulation according to any one of claims 7 to 9, wherein the oil comprises at least one selected from the group consisting of soybean oil, medium chain triglycerides, ethyl oleate, corn oil, and olive oil.
The self-emulsifying oral formulation according to any one of claims 7 to 10, wherein the co-emulsifier comprises at least one selected from the group consisting of ethanol, 1, 2-propanediol, glycerol, polyethylene glycol, diethylene glycol monoethyl ether.
The self-emulsifying oral formulation according to any one of claims 7 to 11, wherein the pharmaceutical carrier comprises:

10 to 50 parts by weight of the oil;

40-80 parts by weight of the emulsifier; and

5-30 parts by weight of the co-emulsifier.
The self-emulsifying oral formulation according to any one of claims 7 to 12, wherein the pharmaceutical carrier comprises:

10 to 35 parts by weight of the oil;

50-70 of the emulsifier; and

10-25 parts by weight of the co-emulsifier.
The self-emulsifying oral formulation according to any one of claims 7 to 13, wherein the pharmaceutical carrier comprises:

25 to 35 parts by weight of the medium chain triglyceride;

50-65 parts by weight of the caprylic/capric polyethylene glycol glyceride; and

10-15 parts by weight of diethylene glycol monoethyl ether.
The self-emulsifying oral formulation according to any one of claims 7 to 11, wherein the pharmaceutical carrier comprises:

0 to 5 parts by weight of the oil;

0-5 parts by weight of the co-emulsifier;

90-100 parts by weight of the emulsifier.
The self-emulsifying oral formulation according to claim 15, wherein said emulsifier consists of at least two emulsifiers.
The self-emulsifying oral formulation according to claim 15, wherein the emulsifier comprises a first emulsifier and a second emulsifier, and the mass fraction of the first emulsifier is 20 to 80% and the mass fraction of the second emulsifier is 10 to 70% based on the total mass of the self-emulsifying oral formulation.
The self-emulsifying oral formulation according to any one of claims 7 to 11 and 15 to 17, wherein the pharmaceutical carrier is constituted by the emulsifier.
The self-emulsifying oral formulation according to any one of the preceding claims, wherein the self-emulsifying oral formulation is in the form of a hard capsule, a soft capsule or a tablet.
The self-emulsifying oral formulation according to any one of claims 1 to 19, comprising:

18.2g of the essential oil of eucalyptus,

16.4g of limonene, 16.4g,

1.8g of alpha-pinene,

181.8g of soybean oil,

145.4g of Tween 80, and the weight ratio of Tween 80,

36.4g of propylene glycol; or

73.3g of eucalyptol, namely,

33.3g of limonene, 33.3g,

26.6g of alpha-pinene,

26.7g of a medium chain triglyceride,

213.4g of caprylic capric acid polyethylene glycol glyceride,

26.7g diethylene glycol monoethyl ether; or

14.6g of eucalyptol, namely,

16.4g of limonene, 16.4g,

5.4g of alpha-pinene,

90.9g of a medium chain triglyceride,

236.6g of caprylic capric acid polyethylene glycol glyceride,

36.4g diethylene glycol monoethyl ether; or

86.6g of eucalyptol, namely,

40.0g of limonene was added as a mixture,

6.6g of alpha-pinene,

93.4g of a medium chain triglyceride,

133.4g of caprylic capric acid polyethylene glycol glyceride,

40g of diethylene glycol monoethyl ether; or

53.3g of the following eucalyptol,

53.3g of limonene was added as a mixture,

26.6g of alpha-pinene,

26.7g of ethyl oleate are added to the solution,

160.1g of a polyoxyethylene castor oil,

80.0g diethylene glycol monoethyl ether; or

78.0g of eucalyptol, the rest of the ingredients are added,

36.0g of limonene was added as a mixture,

6.0g of alpha-pinene,

126g of corn oil, namely, corn oil,

140g of a polyoxyethylene hydrogenated castor oil,

14.0g propylene glycol; or

42.7g of eucalyptol, namely,

28.0g of limonene was added as a mixture,

9.3g of alpha-pinene,

80g of soybean oil (80 g),

180g of Tween 80, and a carrier liquid,

60g of PEG-400; or

69.3g of eucalyptol, namely,

45.5g of limonene was added as a mixture,

15.2g of alpha-pinene,

40g of corn oil, namely corn oil,

170g of a polyoxyethylene castor oil,

60g of propylene glycol; or

70.0g of eucalyptol is added,

45.5g of limonene was added as a mixture,

14.5g of alpha-pinene,

40g of soybean oil (soy bean oil),

180g of polyoxyethylene hydrogenated castor oil,

50g of propylene glycol; or

70.0g of eucalyptol is added,

45.5g of limonene was added as a mixture,

14.5g of alpha-pinene,

50g of ethyl oleate are added to the mixture,

160g of caprylic capric acid polyethylene glycol glyceride,

60g of diethylene glycol monoethyl ether; or

69.3g of eucalyptol, namely,

45.5g of limonene was added as a mixture,

15.2g of alpha-pinene,

40g of soybean oil (soy bean oil),

170g of Tween 80, and a pharmaceutically acceptable carrier,

60g of propylene glycol; or

69.3g of eucalyptol, namely,

45.5g of limonene was added as a mixture,

15.2g of alpha-pinene,

40g of soybean oil (soy bean oil),

170g of Tween 80, and a pharmaceutically acceptable carrier,

60g of propylene glycol; or

75g of the eucalyptus oil is added,

50g of limonene (a) was added,

16g of alpha-pinene, and the like,

79g of Tween 80, and a preparation method thereof,

180g caprylic capric acid polyethylene glycol glyceride; or

75g of the eucalyptus oil is added,

50g of limonene (a) was added,

16g of alpha-pinene, and the like,

165g of caprylic capric acid polyethylene glycol glyceride,

94g of polyoxyethylated castor oil.
A process for preparing the self-emulsifying oral formulation of any preceding claim, comprising:

mixing said active ingredient with said pharmaceutical carrier so as to obtain said self-emulsifying oral formulation.
The method of claim 21, further comprising encapsulating a mixture comprising the active ingredient and the pharmaceutical carrier to obtain a formulation.
The method of claim 22, wherein the formulation is a soft capsule, a hard capsule, or a tablet.
The method of claim 21, wherein mixing the active ingredient with the pharmaceutical carrier further comprises:

subjecting the active ingredient and optionally the fat to a first mixing treatment so as to obtain an oily phase mixture;

and carrying out second mixing treatment on the oil-phase mixture, the emulsifier and the optional coemulsifier.
The method of claim 24, wherein the first mixing process and the second mixing process are each independently performed under the following conditions:

the temperature is 15-30 ℃;

the stirring speed is as follows: 30-50 rpm; and/or

The mixing time is 1-2 hours.
Use of the self-emulsifying oral formulation of any one of claims 1-20 in the manufacture of a medicament for the treatment or prevention of a respiratory disease.
The use of claim 26, wherein the respiratory disease comprises: acute sinusitis, chronic sinusitis, sinusitis operation inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary disease, pulmonary fungal infection, pulmonary tuberculosis, and silicosis.
A method for treating or preventing a respiratory disease, which comprises administering the self-emulsifying oral preparation according to any one of claims 1 to 20 to a patient suffering from a respiratory disease.
The method of claim 28, wherein the respiratory disease comprises: acute sinusitis, chronic sinusitis, sinusitis operation inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary disease, pulmonary fungal infection, pulmonary tuberculosis, and silicosis.