CN103585641A - Lipid coating and cyclodextrin inclusion synergic flavoring method and related preparation thereof - Google Patents

Abstract

The invention discloses a coordinative flavoring method of lipid encapsulation and cyclodextrin inclusion and its related preparations. After the preparation enters the oral cavity, the lipid encapsulation can prevent most of the drugs from dissolving, so that the local drug concentration is low. Although a small amount of drugs are still It will dissolve, but the cyclodextrin can quickly further form inclusion complexes to prevent its bitter groups from contacting the taste buds. taste effect. The taste-correcting method has good taste-masking and taste-correcting effects on various bitter tastes and drugs with different doses, and has a wide application range, simple process, and easy industrialization. The inclusion of lipid encapsulation and cyclodextrin reduces the dosage of cyclodextrin, reduces the cost of excipients, improves oral experience, and facilitates the preparation of related preparations.

Description

A synergistic flavoring method of lipid encapsulation and cyclodextrin inclusion and related preparations

technical field

The present invention relates to the field of pharmaceutical preparations. Specifically, the present invention relates to a synergistic flavoring method for lipid encapsulation and cyclodextrin inclusion of drugs. Methods The lipid microspheres/particles were condensed, and then the preparation was prepared by mixing the lipid microspheres/particles with the optimal amount of cyclodextrin obtained through calculation.

Background technique

Among the descriptions of the properties of 771 chemical entities included in the first part of the second volume of the "Pharmacopoeia of the People's Republic of China" in 2010, 1/3 of the commonly used drugs have varying degrees of bitterness. In addition, some medicines have unpleasant tastes such as pungent, sour, and salty. The taste of medicines can affect patients' compliance with taking medicines. For drugs with poor taste, the preparation development process often uses different technologies to cover up the bad taste.

Existing preparation flavoring technology mainly contains:

(1) Flavoring agents: By adding sweeteners, sour agents, cooling agents, warming agents, mucilage agents, aromatic agents and other flavoring agents, the taste buds can enhance the taste buds' perception and smell of sweet, sour, cool, hot, slippery The nerve's perception of fragrance confuses the brain's sense of taste and masks the bitterness of the drug. A large amount of patents such as CN1124618, CN1883506, CN102370664A, CN101890049A, US5272137 and so on are all this method, and this method is simple, and is effective to the medicine of small dose mouthfeel slightly bitter, but to the medicine of large dose and strong bitter taste, then effect is not good, and taste is modified The drug has no therapeutic effect for the patient, and for special patients, there may be some side effects;

(2) Granulation: Mix bitter medicine with sweetener, hydrophobic polymer, wax lipid, etc., and granulate by dry method, wet method or melting method. Such as US6126967 and other patents. This method is economical and convenient, but for drugs with large doses and strong bitterness, some bitterness can still be felt;

(3) Coating: Coating is one of the most effective and commonly used taste masking techniques. Such as CN1803128, 200410007552, US7294347, US6551617 and other patents. Coating method is one of the most effective flavor correction methods, but the taste masking effect depends on the integrity of the coating, and the process is more complicated;

(4) Cyclodextrin inclusion: Cyclodextrin inclusion can mask the bitter group of the drug, so as to achieve the taste-correcting effect. Such as CN102600119A, CN1176784, CN102349915A and other patents. The disadvantage of this method is that if the drug needs to be completely included, the amount of cyclodextrin is relatively large, which brings inconvenience to the preparation process;

(5) Lipid particles: mix bitter medicine with melted low-melting point waxy lipid substances, form lipid microspheres after freezing, use lipid skeleton to reduce the combination of medicine and taste buds, and cover up the bad taste of medicine. industrialization. Such as CN1739523, US5320848 and other patents. The disadvantage of this method is that it is difficult to completely mask the bitter taste. A small amount of the drug will dissolve and contact the taste buds within a short time after entering the oral cavity, and a small amount of bitter taste can still be perceived.

After the formulation enters the oral cavity, lipid encapsulation can prevent most of the drug from dissolving, so that the local drug concentration is low. Although a small amount of drug will still dissolve, cyclodextrin can quickly further form an inclusion complex with it to prevent its bitter group from contacting the taste buds , under the action of this synergistic flavoring system, the local drug concentration becomes lower, thereby obtaining better flavoring effect. The taste-correcting method has good taste-masking and taste-correcting effects on various bitter tastes and drugs with different doses, and has a wide application range, simple process, and easy industrialization. The inclusion of lipid encapsulation and cyclodextrin reduces the dosage of cyclodextrin, reduces the cost of excipients, improves oral experience, and facilitates the preparation of related preparations.

Contents of the invention

An object of the present invention is to provide a synergistic taste-correcting method, which has good taste-masking and taste-correcting effects for various doses and different bitter medicines, and has a simple process and is easy to industrialize. The minimum amount of cyclodextrin is obtained by calculation under the premise of the effect, which is convenient for the preparation of related preparations in the later stage.

The technical problem to be solved by the present invention adopts the following technical solutions to realize:

A lipid encapsulation and cyclodextrin inclusion synergistic flavoring method, using excipients to carry out lipid encapsulation and cyclodextrin inclusion of drugs to prepare a preparation. After the preparation enters the oral cavity, the lipid encapsulation can prevent most of the drugs from dissolving. The local drug concentration is low, although a small amount of drug will still dissolve, but the cyclodextrin can quickly further form an inclusion compound with it to prevent its bitter group from contacting the taste buds. Under the action of the synergistic flavor system, the local drug concentration becomes lower, resulting in a better flavoring effect. The taste-correcting method has good taste-masking and taste-correcting effects on various bitter tastes and drugs with different doses, and has a wide application range, simple process, and easy industrialization. The inclusion of lipid encapsulation and cyclodextrin reduces the dosage of cyclodextrin, reduces the cost of excipients, improves oral experience, and facilitates the preparation of related preparations.

The auxiliary materials are lipid skeleton material and polymer material for lipid encapsulation, and cyclodextrin for encapsulation.

The lipid skeleton material includes stearic acid, stearyl alcohol, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, solid paraffin, cetyl alcohol, stearyl alcohol and cocoa butter, etc. One or more of, preferably stearyl alcohol.

The high molecular material includes natural glue polymers such as gum arabic and gelatin, hydrophilic cellulose polymers, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone (PVP), alginic acid and alginic acid One or more of salt, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), Eudragit, etc., preferably Eudragit.

In the synergistic flavoring preparation, the molar ratio of cyclodextrin to drug is 1:10-10:1.

The cyclodextrins include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, δ-cyclodextrin, carboxymethyl β-cyclodextrin, thio-β-cyclodextrin, hydroxypropyl-β - one or more of cyclodextrin and sulfobutyl ether - beta-cyclodextrin, preferably beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.

The flavor-correcting medicine can be prepared into various forms of oral preparations through pharmacy methods, including ordinary tablets, capsules, orally disintegrating tablets, dispersible tablets, dry suspensions, suspensions, and the like.

The present invention weighs one or more lipid skeleton materials and/or macromolecular materials according to the prescription amount, heats and melts them, and after they are melted, adds micronized medicines passing through a sieve with a specified mesh in a certain proportion, and mixes them uniformly to form Uniform melt or suspension is solidified by a certain method, the particles are collected, sieved, and the particles of the specified mesh are taken to obtain lipid flavored microspheres/granules;

Wherein lipid flavor-correcting microspheres/particles comprise 20-75wt%, preferably 25-70wt%, most preferably 30-65wt% lipid skeleton material; 1-30wt%, preferably 1-25wt%, most preferably 1-20wt% % polymer material; 5-45wt%, preferably 10-40wt%, most preferably 15-35wt% of the drug;

After determining the drug specification and drug bitterness threshold concentration in the preparation, the minimum amount of cyclodextrin used for synergistic flavor correction can be obtained by calculation. Taking paracetamol as an example, the specific calculation process and synergistic flavor principle are as follows:

A preparation composed of a mixture of lipid-encapsulated microspheres and β-cyclodextrin, when encountering water (saliva), in the kinetic model of inclusion of lipid-encapsulated and β-cyclodextrin molecules, the drug is divided into encapsulated, free, Contains three parts;

When the lipid microspheres are mixed with β-cyclodextrin and encounter water (saliva), the release behavior of the drug (X ₁ ) encapsulated in the microspheres conforms to the first-order release model. Since the time of the drug in the oral cavity is very short, The rate of free drug entering the lipid microsphere in the solution (saliva) can be approximated as 0. At this time, the initial drug amount in the lipid-encapsulated microsphere is D, and the release rate constant is k, then:

$\frac{{\mathrm{<span\; class="notranslate">\; <figure-callout\; id="1"\; label="wxya"\; filenames="DEST\_PATH\_HDA0000431013860000011.png,DEST\_PATH\_HDA0000431013860000041.png"\; state="\{\{state\}\}">wxya</figure-callout></span>}}_{\mathrm{<span\; class="notranslate">\; 1</span>}}}{\mathrm{<span\; class="notranslate">\; dt</span>}}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; -</span>{\mathrm{<span\; class="notranslate">\; wxya</span>}}_{\mathrm{<span\; class="notranslate">\; 1</span>}}<span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; )</span>$

The amount of drug free in saliva (X ₂ ) is equal to the released amount minus the amount of drug in the β-cyclodextrin inclusion complex (X ₃ ), namely:

X ₂ =DX ₁ -X ₃ (2)

Since the reaction rate of β-cyclodextrin and paracetamol is much faster than the release rate of lipid-encapsulated microspheres, it can be considered that the two quickly reach equilibrium [Li HY, Ge JW, Guo T, et al. Determination of the kinetic rate constant of cyclodextrin supramolecular systems by high performance affinity chromatography[J].J Chromatogr A,2013,1305:139-148.], so X3 is mainly composed of β-cyclodextrin concentration Y, equilibrium constant K of β-cyclodextrin and paracetamol and X2 decide, namely:

X ₃ =KX ₂ Y (3)

At the same time, assuming that the molar ratio of drug to β-cyclodextrin in the clathrate is 1:1, and the initial concentration of β-cyclodextrin in the solution is Y ₀ , then:

Y=Y ₀ -X ₃ (4)

Solve for X ₁ , X ₂ , X ₃ , Y to get:

X ₁ =D e ^-kt (5)

${\mathrm{<span\; class="notranslate">\; x</span>}}_{\mathrm{<span\; class="notranslate">\; 2</span>}}<span\; class="notranslate">\; =</span>\frac{{\mathrm{<span\; class="notranslate">\; e</span>}}^{<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; kt</span>}}}{\mathrm{<span\; class="notranslate">\; 2</span>}\mathrm{<span\; class="notranslate">\; K</span>}}<span\; class="notranslate">\; (</span>\sqrt{{<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; KD</span>}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; Ky</span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>{\mathrm{<span\; class="notranslate">\; KD</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; )</span>}^{\mathrm{<span\; class="notranslate">\; 2</span>}}<span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 4</span>}\mathrm{<span\; class="notranslate">\; KD</span>}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; (</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; )</span>}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; KD</span>}<span\; class="notranslate">\; -</span>{\mathrm{<span\; class="notranslate">\; Ky</span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; KD</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; 6</span>}<span\; class="notranslate">\; )</span>$

${\mathrm{<span\; class="notranslate">\; x</span>}}_{\mathrm{<span\; class="notranslate">\; 3</span>}}<span\; class="notranslate">\; =</span>\frac{\mathrm{<span\; class="notranslate">\; 1</span>}}{\mathrm{<span\; class="notranslate">\; 2</span>}}<span\; class="notranslate">\; (</span>{\mathrm{<span\; class="notranslate">\; <figure-callout\; id="0"\; label="Y"\; filenames="DEST\_PATH\_HDA0000431013860000011.png,DEST\_PATH\_HDA0000431013860000021.png"\; state="\{\{state\}\}">Y</figure-callout></span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}<span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; D.</span>}<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; -</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; +</span>\frac{\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; -</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; kt</span>}}\sqrt{{<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; KD</span>}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; Ky</span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; KD</span>}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; )</span>}^{\mathrm{<span\; class="notranslate">\; 2</span>}}<span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 4</span>}\mathrm{<span\; class="notranslate">\; KD</span>}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; (</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; )</span>}}{\mathrm{<span\; class="notranslate">\; K</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; 7</span>}<span\; class="notranslate">\; )</span>$

$\mathrm{<span\; class="notranslate">\; Y</span>}<span\; class="notranslate">\; =</span>\frac{\mathrm{<span\; class="notranslate">\; 1</span>}}{\mathrm{<span\; class="notranslate">\; 2</span>}}<span\; class="notranslate">\; (</span>{\mathrm{<span\; class="notranslate">\; <figure-callout\; id="0"\; label="Y"\; filenames="DEST\_PATH\_HDA0000431013860000011.png,DEST\_PATH\_HDA0000431013860000021.png"\; state="\{\{state\}\}">Y</figure-callout></span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}<span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; D.</span>}<span\; class="notranslate">\; (</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; +</span>\frac{{\mathrm{<span\; class="notranslate">\; e</span>}}^{<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; kt</span>}}\sqrt{{<span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; KD</span>}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; +</span>{\mathrm{<span\; class="notranslate">\; Ky</span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; KD</span>}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; )</span>}^{\mathrm{<span\; class="notranslate">\; 2</span>}}<span\; class="notranslate">\; +</span>\mathrm{<span\; class="notranslate">\; 4</span>}\mathrm{<span\; class="notranslate">\; KD</span>}{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; (</span>{\mathrm{<span\; class="notranslate">\; e</span>}}^{\mathrm{<span\; class="notranslate">\; kt</span>}}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1</span>}<span\; class="notranslate">\; )</span>}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; 1</span>}}{\mathrm{<span\; class="notranslate">\; K</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; -</span><span\; class="notranslate">\; (</span>\mathrm{<span\; class="notranslate">\; 8</span>}<span\; class="notranslate">\; )</span>$

The amount of β-cyclodextrin was determined according to the formula (6), and the synergistic flavor delivery system of lipid encapsulation and β-cyclodextrin inclusion was obtained.

Lipid microspheres can regulate k to control drug release, and β-cyclodextrin encapsulates the drug released by lipid microspheres. Therefore, the local drug concentration will become lower after lipid encapsulation and molecular inclusion, thus obtaining Better synergistic flavoring effect.

The beneficial effects of the present invention are: the taste-correcting method of the present invention has good taste-masking and taste-correcting effects for various bitter tastes and medicines of different doses, has a wide application range, simple process, and is easy to be industrialized; On the premise of the effective effect, the combination of lipid encapsulation and cyclodextrin inclusion can reduce the dosage of cyclodextrin, reduce the cost of auxiliary materials and improve oral experience, and facilitate the preparation of related preparations.

Description of drawings

Fig. 1 is the release curve of the acetaminophen lipid-corrected flavor microspheres prepared by the prescription of Example 1 and the bulk drug of the present invention;

Fig. 2 is the release curve of the paracetamol lipid flavoring granules prepared by the prescription of Example 2 and the bulk drug of the present invention;

Fig. 3 is the release curve of the ibuprofen lipid flavored microspheres prepared by the prescription of Example 3 and the crude drug of the present invention;

Fig. 4 is the nuclear magnetic resonance spectrum of the paracetamol lipid microsphere-β-cyclodextrin synergistic flavoring system solution prepared according to the prescription of Example 4 of the present invention.

Detailed ways

In order to make the technical means, creative features, goals and effects achieved by the present invention easy to understand, the present invention will be further described below in conjunction with specific illustrations.

Embodiment one:

Paracetamol Lipid Microspheres

prescription:

Preparation steps:

1) Weigh the prescription amount of stearyl alcohol, heat and melt;

2) Add Eudragit in the prescribed amount, wait for it to melt, and stir to form a uniform molten liquid;

3) Add the prescribed amount of paracetamol, and mix evenly with magnetic stirring,

4) Spray the suspension quickly with a spray gun, collect the particles, sieve, and take the particles with the specified mesh to obtain the lipid flavored microspheres.

The physicochemical properties and taste of the prepared flavoring granules were tested by morphological characterization and dissolution test.

(1) Morphological characterization: The appearance of lipid microspheres was observed under an inverted phase contrast microscope, and the particle size distribution of lipid microspheres was measured using a Camsizer XP particle size analyzer compressed air dispersion sampling method (X-Jet) at an air pressure of 30kPa And morphology, such as sphericity (SPHT), symmetry (Symm), aspect ratio (b/I).

After inspection, the boundary of the solid lipid microsphere obtained in the present invention is round, the sphericity (SPHT) is relatively high, the average value reaches 0.949, and the average symmetry factor (Symm) is 0.953. The surface morphological characteristics of the granules mainly affect the taste by affecting the dissolution of the drug. The smoother and more regular the surface of the granules, the lower the dissolution rate and the better the taste modification [Beatrice A, Cristina C, Nadia P, et al.Characterization and taste-masking evaluation of acetaminophen granules: comparison between different preparation methods in a high-shear mixer [J]. Eur J Pharm Sci, 2004, 21: 295-303.]. The solid lipid microsphere of the invention can effectively reduce its surface area, slow down the dissolution rate of medicine in a short time, and significantly improve the taste-correcting effect.

(2) Dissolution test: Dissolution testing method (Chinese Pharmacopoeia 2010 edition 2 appendix XC second method paddle method) was used, 200mL of distilled water was used as the dissolution medium, and the rotation speed was 50rpm. Take lipid microspheres with a drug content of 20 mg, take 2 mL of the solution at 10, 30, 60, 90, 120, 180, 240, and 300 s respectively, filter with a 0.22 μm microporous membrane, discard the initial filtrate, and take the continued The filtrate is ready for use, and immediately replenish the same volume of blank medium solution in the operating container. The concentration of acetaminophen in the filtrate was determined by HPLC, the average cumulative release percentage was calculated, and the dissolution rate of the paracetamol bulk drug was measured simultaneously as a parallel comparison. Chromatographic conditions for HPLC determination of paracetamol content: Chromatographic column: Phenomenex C18 bonded silica gel column (15cm×4.6mm, 5μm); mobile phase: methanol: phosphate buffer (pH4.5) = 20:80; column temperature: 25°C ; Flow rate: 1.0mL/min; Injection volume: 10μL; UV detection wavelength: 254nm.

As shown in Figure 1, after inspection, the paracetamol raw material drug release rate is extremely fast under the condition of 37 ℃ sink, the release rate reaches more than 70% within 30s, and it is almost completely released within 120s. In contrast, solid lipid microspheres have obvious slow-release effect, stearyl alcohol lipid skeleton and Eudragit can inhibit drug release, and the slow-release effect is obvious. Flavored granules have almost no release in 10s, and only insufficient release in 30s 2%, release 6% in 60s, release about 35% in 300s, with obvious taste masking effect.

Embodiment two:

paracetamol lipid particles

prescription:

Preparation steps:

1) Weigh the prescribed amount of paracetamol and add it to hot water;

2) Add stearyl alcohol, monoglyceride, and cocoa butter in the prescribed amount to make it melt;

3) After maintaining constant temperature magnetic stirring for a certain period of time, turn off the heating switch, and adjust the magnetic stirring to an appropriate speed until the system cools down to room temperature;

4) The suspension is taken out, filtered, and dried to obtain paracetamol lipid-flavored granules.

The taste of the prepared flavoring granules was tested by dissolution test. The experimental method is as in Example 1.

See Figure 2. After testing, solid lipid particles have a certain slow-release effect compared with raw materials, and the lipid skeleton can inhibit drug release. The release of flavor-correcting granules is less than 20% in 30s and 40% in 60s. It has a certain taste-masking effect when it does not stay in the mouth for more than 60s.

Embodiment three:

Ibuprofen Lipid Microspheres

prescription:

Preparation steps:

1) Weigh the prescription amount of stearyl alcohol, heat and melt;

2) Add the prescribed amount of ibuprofen, stir evenly with magnetic force,

3) Spray the suspension quickly with a spray gun, collect the particles, sieve, and take the particles with the specified mesh to obtain the lipid flavoring microspheres.

The physicochemical properties and taste of the prepared flavoring granules were tested by morphological characterization and dissolution test.

(1) Morphological characterization: Observe the appearance of lipid microspheres under an inverted phase-contrast microscope. Under 200 times magnification (100 μm scale), the surface of the flavor-correcting particles is smooth and flat, with good fluidity, which is convenient for post-processing and application .

(2) Dissolution test: the method is the same as in Example 1. Chromatographic conditions for HPLC determination of ibuprofen content Chromatographic column: C18 (25cm×4.6mm, 5μm); mobile phase: acetate buffer: acetonitrile = 40:60; detection wavelength: 263nm; flow rate: 1.0mL/min; Column temperature: 25°C.

As shown in Figure 3, the release rate of the ibuprofen bulk drug is relatively fast under the sink condition of 37°C, and the release rate reaches more than 35% within 30s, and more than 90% is released within 120s. In contrast, the solid lipid microspheres of this prescription have a certain sustained-release effect, and the stearyl alcohol lipid skeleton can inhibit the release of the drug, and the sustained-release effect is obvious. The flavored granules only release less than 6% in 30s, and 25% in 60s. About 97% is released in 300s, which has a more obvious taste masking effect.

Embodiment four:

Paracetamol lipid microspheres-β-cyclodextrin synergistic flavoring system

After calculation, the minimum amount of β-cyclodextrin and paracetamol flavored microspheres combined is obtained, and the mass ratio of β-cyclodextrin to paracetamol is 6.8:1.

The paracetamol lipid microsphere-β-cyclodextrin synergistic flavoring system was obtained by physically mixing β-cyclodextrin with the lipid microspheres of Example 1 at a ratio of 6.8:1.

The physical and chemical properties and taste of the obtained synergistic flavor system were tested by nuclear magnetic resonance and electronic tongue measurement. See Figure 4.

(1) NMR test: Take paracetamol, β-cyclodextrin, lipid microspheres, lipid microspheres-cyclodextrin flavored particles, and paracetamol-cyclodextrin flavored powders with a drug content of about 10 mg. Place in 10mL water at 37°C and shake at 50rpm for 5min, filter with a 0.22μm microporous membrane, discard the initial filtrate, take the subsequent filtrate to freeze-dry and redissolve in _D2O , use liquid NMR to characterize the composition of the reconstituted solution Element.

After inspection, in ^{the 1} H NMR spectrum, paracetamol has three characteristic peaks: double peaks H-2 and H-6 at 7.12ppm; double peaks H-3 and H-5 at 6.78ppm; and 2.01ppm CH ₃ singlet at . After adding β-cyclodextrin, the chemical shift values of the three types of protons all increase, and the change is more obvious with the increase of β-cyclodextrin, but it has nothing to do with the addition of microspheres (the chemical shift values of B and C ₂ <0.005ppm). With the increase of β-cyclodextrin dosage (C ₁ , C ₂ ), H-2 and H-6 increased by 0.04 and 0.06ppm respectively; the methyl peak increased by 0.02 and 0.02ppm, but H-3 and H- 5 The increase is not obvious. At the same time, the proton chemical shift values of β-cyclodextrin decreased with the addition of paracetamol. Therefore, the above results indicate that paracetamol interacts with β-cyclodextrin to form inclusion complexes.

(2) Electronic tongue experiment: α-Astree electronic tongue II with 16-position autosampler and 80mL sample cell was used for measurement. Each sample was measured seven times, each time 2min, and the data at 120s was selected for statistical analysis. Put 80mL of pure water into the cleaning pool between each sample. PCA and DFA analyzes were performed on the data using Alphasoft V12 workstation software. Preparation of sample solution: Accurately weigh about 0.30, 1.00, 3.00, 10.00 mg of paracetamol (API-0.3, API-1, API-3, API-10) in 80 mL of pure water as the raw material control solution (A). The device adopts the dissolution method (the paddle method of the second appendix XC of the 2010 edition of the Chinese Pharmacopoeia), and operates according to the law. 100mL of distilled water was used as the dissolution medium, and the rotation speed was 50rpm. Take lipid microspheres (M) and lipid microspheres-cyclodextrin flavored particles with a drug content of about 10 mg respectively (the mass ratio of paracetamol in lipid microspheres to β-cyclodextrin is 1: 3.37 and 1:6.74 are fully mixed, recorded as C ₁ , C ₂ ), paracetamol-cyclodextrin flavoring powder (API-β-CD, paracetamol and β-cyclodextrin at a mass ratio of 1:6.8, fully mixed ), at 30s, quickly filter the eluate, and take 80mL of the filtrate for use.

PCA analysis was performed on the paracetamol crude drug control group and the measured values of the dissolution liquid of each sample at 30 s to obtain its taste spectrum. The results showed that the spectrum distribution of the raw drug control solution was concentrated, and moved to the right as the concentration increased, and the lipid-encapsulated microspheres, β-cyclodextrin-paracetamol flavored powder and the paracetamol raw material drug could be separated well, both It is located on the left side of the API, indicating that both lipid-encapsulated microspheres and β-cyclodextrin inclusion compounds have obvious flavor-correcting effects; The spectra of lipid-encapsulated microspheres partially overlapped, indicating that lipid-encapsulated microspheres played a major role in this synergistic flavor system. Adding a small amount of β-cyclodextrin (C ₁ ) to lipid-encapsulated microspheres has a taste similar to that of lipid particles, but with the increase of β-cyclodextrin (C ₂ ), the flavoring effect of the synergistic flavoring system further improved.

Embodiment five:

Paracetamol Lipid Microspheres-β-Cyclodextrin Synergistic Orally Disintegrating Tablets

Tablet Prescription:

Preparation steps:

1) Prepare 10% gelatin solution;

2) Weigh β-cyclodextrin and sucralose according to the prescription, and dissolve them with an appropriate amount of deionized water to obtain a clear solution;

3) Mix the solution prepared in 2) with the prescribed amount of gelatin solution evenly, and add deionized water to 200mL;

4) Add the prescribed amount of flavoring granules, disperse evenly, and quickly dispense into freeze-drying molds with a volume of 0.8mL;

5) The mold was dried in a freeze dryer to obtain 250 orally disintegrating tablets.

The specific freeze-drying parameters and process are as follows: send it into a freeze-drying machine, quickly cool down to -40°C and below, ensure that the tablets obtained under low-temperature compression are frozen solid, keep warm for 1 hour, turn on the vacuum pump, and keep the vacuum pressure at 1-20Pa, at a rate of each Slowly raise the temperature to -25°C at a heating rate of 1-5°C per hour, keep warm for 12 hours, then slowly raise the temperature to -5°C at a heating rate of 1-5°C per hour, keep warm for 8 hours, the first drying stage ends, and then Slowly raise the temperature to 25°C at a heating rate of 1-5°C per hour, keep it warm for 8 hours, and pack it after leaving the box.

Referring to the quality control requirements for orally disintegrating tablets in the United States Pharmacopoeia, the Japanese Pharmacopoeia and the Chinese Pharmacopoeia, the following detection methods were developed for the key parameters of low-temperature compressed freeze-dried orally disintegrating tablets.

Disintegration time: The device is mainly composed of a dissolution cup, a stirring paddle, and a disintegration basket (30 mesh mesh), add 900mL of 37°C distilled water into the dissolution cup, fix the disintegration basket on the wall of the dissolution cup, and the water surface exceeds the bottom of the basket 1cm, the stirring speed is adjusted to 100rpm, the orally disintegrating tablet is put into the disintegration basket, and the time from when the tablet is put into the screen until there is basically no residue on the screen is recorded as the disintegration time of the orally disintegrating tablet, and the disintegration time limit is required to be within 30s party meets the requirements.

Friability: The friability of orally disintegrating tablets is measured by the air drop method, that is, the tablet is dropped from a height of 0.3m in free fall three times in sequence, and falls onto a flat glass plate, and then the oral disintegration is measured. Tablet mass loss, calculated friability (%).

After inspection, the disintegration time limit of the obtained rapidly disintegrating tablet was 15.7s, and the friability was 0.02%, which met the preparation standard. After tasting, the preparation tastes good without obvious bitterness.

Embodiment six:

Paracetamol Lipid Granules-Hydroxypropyl-β-Cyclodextrin Collaborative Flavor Orally Disintegrating Tablets

Tablet Prescription:

The acetaminophen lipid particle in Example 2 was physically mixed with the prescribed amount of hydroxypropyl-β-cyclodextrin to obtain a paracetamol lipid particle hydroxypropyl-β-cyclodextrin synergistic flavoring system.

Tablet Prescription:

The preparation steps of the orally disintegrating tablet are the same as in Example 5.

The freeze-drying process, freeze-drying parameters, disintegration time limit and friability detection are as described in Example 5. Get 250 orally disintegrating tablets.

After inspection, the disintegration time limit of the obtained rapidly disintegrating tablet was 18.6s, and the friability was 0.06%, which met the preparation standard. After tasting, the preparation has a good mouthfeel and no obvious unpleasant taste.

Embodiment seven:

Orally disintegrating tablets based on ibuprofen lipid microspheres-β-cyclodextrin synergistic flavoring system

Tablet Prescription:

Preparation steps:

1) Prepare 10% gelatin solution;

2) Weigh β-cyclodextrin and sucralose according to the prescription, and dissolve them with an appropriate amount of deionized water to obtain a clear solution;

3) Mix the solution prepared in 2) with the prescribed amount of gelatin solution evenly, and add deionized water to 200mL;

4) Add the prescribed amount of flavoring granules, disperse evenly, and quickly dispense into freeze-drying molds with a volume of 0.8mL;

5) The mold was dried in a freeze dryer to obtain 250 orally disintegrating tablets.

The freeze-drying process, freeze-drying parameters, disintegration time limit and friability detection are as described in Example 5.

After inspection, the disintegration time limit of the obtained rapidly disintegrating tablet was 17.7s, and the friability was 0.07%, which met the preparation standard. After tasting, the preparation has a good mouthfeel and no obvious unpleasant taste.

Embodiment eight:

Dry suspension based on ibuprofen lipid microspheres-β-cyclodextrin synergistic flavoring system

prescription:

Preparation steps:

1) Dry the drugs and excipients in the prescription separately and pass through a 200-mesh sieve;

2) Mix evenly to obtain a dry suspension;

The powder was dispersed by adding a certain amount of distilled water. After tasting, the preparation had a good taste and no obvious unpleasant taste.

Embodiment nine:

Suspension based on ibuprofen lipid microspheres-β-cyclodextrin synergistic flavoring system

prescription:

Preparation steps:

1) Take ibuprofen flavored microspheres and place them in a mortar;

2) Add glycerin and mix thoroughly to form a fine paste;

3) Add HPMC aqueous solution and stir;

4) Add distilled water to the mark and stir evenly to obtain a suspension.

After tasting, the preparation has a good mouthfeel and no obvious unpleasant taste.

The basic principles and main features of the present invention and the advantages of the present invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above-mentioned embodiments. What are described in the above-mentioned embodiments and the description only illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will also have Variations and improvements are possible, which fall within the scope of the claimed invention. The protection scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

1. a lipid wraps up and the collaborative method to modify taste of cyclodextrin inclusion compound, it is characterized in that: utilize adjuvant to carry out lipid parcel and cyclodextrin inclusion compound to medicine, be prepared into preparation, at preparation, enter behind oral cavity, lipid parcel can stop contacting of most of medicine dissolution and taste bud, cyclodextrin inclusion compound can further form rapidly clathrate with the medicine of a small amount of dissolving, makes local drug level become lower, thereby obtains better taste masking effect.

2. a kind of lipid parcel according to claim 1 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: described adjuvant is for lipid framework material and macromolecular material for lipid parcel, for the cyclodextrin of enclose.

3. a kind of lipid parcel according to claim 2 and cyclodextrin inclusion compound are worked in coordination with method to modify taste, it is characterized in that: described collaborative method to modify taste concrete operation step is,

1) medicine is mixed and melts or mix and disperse with lipid framework material and macromolecular material heating;

2) by condensation, obtain lipid microsphere/granule;

3) again by lipid microsphere/granule with by calculating the cyclodextrin proportioning of optimum amount, prepare preparation.

4. a kind of lipid parcel according to claim 3 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: under the sink conditions that described preparation is dissolution medium at 37 ℃ of distilled water, in 30s, drug release rate is 1-20%.

5. a kind of lipid parcel according to claim 3 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: described lipid microsphere/granule is by lipid framework material, the macromolecular material of 1-30wt%, the ingredients of 5-45wt% of 20-75wt%.

6. a kind of lipid parcel according to claim 2 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: described lipid framework material is one or more in stearic acid, stearyl alcohol, glyceryl monostearate, Tridocosanoin, palmitic acid stearic acid ester of glycerol, hard paraffin, hexadecanol, octadecanol and cocoa butter.

7. a kind of lipid parcel according to claim 2 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: described macromolecular material be arabic gum, sky hot glue family macromolecule polymer, hydrophilic cellulose base polymer, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, alginic acid and alginate, xanthan gum, hydroxypropyl cellulose and hydroxypropyl emthylcellulose and especially strange etc. in one or more.

8. a kind of lipid parcel according to claim 2 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: described cyclodextrin is one or more in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, δ-cyclodextrin, carboxymethyl beta cyclodextrin, sulfo-beta cyclodextrin, HP-β-CD and sulfobutyl ether-beta-cyclodextrin.

9. a kind of lipid parcel according to claim 3 and the collaborative method to modify taste of cyclodextrin inclusion compound, is characterized in that: the mol ratio of described cyclodextrin and medicine is 1:10-10:1.

10. a kind of lipid parcel according to claim 3 and cyclodextrin inclusion compound are worked in coordination with method to modify taste, it is characterized in that: described preparation can be used for being prepared into multiple oral formulations form, comprises conventional tablet, capsule, oral cavity disintegration tablet, dispersible tablet and suspensoid.

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