CN113350291A - Composition of acetylcholinesterase inhibitor and preparation method thereof - Google Patents

Composition of acetylcholinesterase inhibitor and preparation method thereof Download PDF

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CN113350291A
CN113350291A CN202110229791.5A CN202110229791A CN113350291A CN 113350291 A CN113350291 A CN 113350291A CN 202110229791 A CN202110229791 A CN 202110229791A CN 113350291 A CN113350291 A CN 113350291A
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donepezil
solid dispersion
composition according
carrier material
taste
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石添香
黄心
游劲松
黄芳芳
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Sunshine Lake Pharma Co Ltd
Guangdong HEC Pharmaceutical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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Abstract

The invention relates to a composition of an acetylcholinesterase inhibitor and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The acetylcholinesterase inhibitor composition of the present invention comprises a solid dispersion comprising an acetylcholinesterase inhibitor and a taste-masking carrier. The preparation method comprises the following steps: the acetylcholinesterase inhibitor is mixed with a taste masking carrier, and then the acetylcholinesterase inhibitor solid dispersion is prepared by adopting a hot melt extrusion method or a spray drying method. The acetylcholinesterase inhibitor composition provided by the invention has a good taste masking effect, and the prepared product has good taste and stable quality, does not influence the absorption of the medicine in the body, and ensures the safety and effectiveness of the medicine. The preparation method can simply obtain the composition with better taste masking effect, and can be used in industrial production.

Description

Composition of acetylcholinesterase inhibitor and preparation method thereof
Technical Field
The invention relates to the field of medicinal preparations, in particular to a composition of an acetylcholinesterase inhibitor and a preparation method thereof.
Background
Donepezil hydrochloride (trade name ARICEPT) chemically known as 1-benzyl-4- [ (5, 6-dimethoxy-1-indanon-2-yl) methyl ] piperidine hydrochloride having the following chemical structure:
Figure BDA0002957441050000011
donepezil is a donepezil piperidine oxide, is a second-generation specific reversible central acetylcholinesterase (AChE) inhibitor, and slows down the decomposition of synaptic interstitial acetylcholine (ACh) by inhibiting AChE activity, thereby increasing ACh content and improving cognitive function of Alzheimer's Disease (AD) patients.
Alzheimer Disease (AD), also called senile dementia, is common in the elderly, who are prone to dysphagia. Compared with other dosage forms, the orally disintegrating tablet has the outstanding characteristics of being capable of quickly disintegrating in the oral cavity under the anhydrous condition (or only a small amount of water exists), well solving the problem of swallowing difficulty of old patients and having better compliance. However, the donepezil hydrochloride orally disintegrating tablets sold in the market at present have obvious bitter taste and numb taste, are unacceptable, can reduce the medication compliance of patients, even refuse to take, are not beneficial to the treatment and control of diseases, further influence the social, occupational and life functions of the patients, and inevitably have increasingly deep influence along with the aggravation of the global aging problem.
Patent CN102038653A discloses a method for preparing donepezil hydrochloride orally disintegrating tablets, which uses citric acid, sodium bicarbonate, saccharin sodium and essence as flavoring agents to mask the taste. The method can mask the taste of the medicine with unobvious bitter taste to a certain extent, but has weak effect on the medicine with obvious bitter taste and numb taste, such as donepezil hydrochloride.
Cyclodextrin inclusion is one of the common taste-masking methods, however, the orally disintegrating tablets prepared by the invention are respectively included by hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin and donepezil hydrochloride, and the prepared orally disintegrating tablets still have obvious bitter and numb taste.
Patent WO2009001146 discloses a method for preparing donepezil hydrochloride orally disintegrating tablets using a polacrilin potassium ion exchange resin, which can suppress the bitterness and astringency of donepezil hydrochloride orally disintegrating tablets. However, currently, the ion exchange resin available for medical use is limited, the price is high, the preparation process is complex, and the industrialization difficulty is high. In addition, the complex formed by the drug-ion resin releases the drug in vivo by means of ion exchange, and is greatly influenced by ion concentration, and if the drug is not completely exchanged by ions in vivo when passing through small intestine, incomplete release and reduced absorption can be caused.
The literature Preparation and evaluation of Taste-Masked Donepezil hydrochloride oral dissolution Tablets (Biol Pharm Bull. 2010; 33(8):1364-70.) discloses a method for preparing an Orally Disintegrating tablet using eudragit EPO as a Taste masking material, by dissolving eudragit EPO and Donepezil hydrochloride in a 95% ethanol solution containing aerosil to form a suspension, spray-drying the suspension to form microspheres, and then pressing the microspheres and additional auxiliary materials into an Orally Disintegrating tablet, wherein the Taste masking effect is optimal when the ratio of Donepezil hydrochloride to eudragit EPO is 1: 2. However, the inventors have experimentally assessed that spray drying the granules when the ratio of active ingredient to Esterqi EPO is increased to 1:7 produces a product that is slightly taste masked, but also perceived as significantly bitter and tingling. In addition, the inventor uses the Ettky EPO and the donepezil hydrochloride to carry out hot-melt extrusion, and when the ratio of the active ingredient to the Ettky EPO reaches 1:5, the prepared product still has bitter tingling sensation. In combination with the above two experiments, the inventors considered that the taste-masking effect of ewing EPO on donepezil hydrochloride is relatively limited, and it is difficult to satisfy the effect, and it is not possible to mask the taste of any ewing.
The inventor selects an enteric material for investigation, uses hydroxypropyl methylcellulose acetate succinate (HPMCAS) and donepezil hydrochloride for hot melt extrusion, and the ratio of active ingredients to HPMCAS is 1:5, but the prepared orally disintegrating tablet has obvious bitter tingle irritation and no taste masking effect at all. Neither gastric soluble materials nor enteric soluble materials can achieve taste masking effect.
Patent CN101090737 discloses a method for stabilizing donepezil or its pharmaceutically acceptable salts, which comprises adding high molecular weight acidic substance into the composition of donepezil or its pharmaceutically acceptable salts and high molecular weight basic substance to increase the stability of sustained release preparation, but has no taste masking effect. The invention is according to one of the patent embodiments (example 26): the donepezil hydrochloride and the Ewing L100-55 (methacrylic acid and ethyl acrylate (1:1) copolymer) are subjected to wet granulation and tabletting, and the prepared orally disintegrating tablet has obvious bitter taste and numb taste, is unacceptable and can mask the taste without using the Ewing L100-55.
As described above, in the method of masking a drug having an unpleasant taste, there are cases where the masking effect is poor or it is difficult to perform in the technical field, and thus a method that continues to improve is required.
Disclosure of Invention
Summary of The Invention
The invention aims to disperse donepezil or salts thereof in a carrier material to prepare a solid dispersion, and the donepezil solid dispersion is prepared as taste masking particles by adopting a simple process method such as spray drying, hot melt extrusion and other technologies, and can well mask the bitter taste and the numb taste of raw material medicines after being prepared into an oral preparation, so that the prepared product has good taste and stable quality, does not influence the absorption of the medicines in the body, and ensures the safety and effectiveness of the medicines.
The invention disperses donepezil or its salt in carrier material, and prepares solid dispersion by spray drying or hot melt extrusion, wherein donepezil or its salt exists in amorphous form in the solid dispersion. Generally, the drug exists in an amorphous form and the solubility increases, and if it is made into orally disintegrating tablets, the active ingredient is more easily released after oral disintegration, and thus more active substance comes into contact with taste buds, and if the active substance has a bitter taste, a more bitter taste is felt. However, it was unexpected that a solid dispersion of donepezil or a salt thereof in a solid dispersion with a carrier material could be obtained which had a good taste masking effect. Surprisingly, the carrier material Eudragit L100-55 and donepezil or salt thereof are prepared into a solid dispersion according to a certain proportion, so that the solid dispersion has a good taste masking effect; other carrier materials such as Ettqi EPO, HPMCAS and donepezil or salts thereof cannot mask the taste well after being prepared into solid dispersion.
The donepezil solid dispersion prepared by the spray drying process has small particle size (D90<200um), and does not generate gritty feeling after being prepared into orally disintegrating tablets; the solid dispersion prepared by the hot-melt extrusion process can also obtain smaller particles (D90<200um) by crushing and sieving, and can be prepared into orally disintegrating tablets without generating gravel feeling; and no additional bitterness is brought about by crushing to destroy the particles. Spray drying is a drying method which adopts an atomizer to disperse raw material liquid into fog drops and uses hot gas (air, nitrogen or superheated steam) to dry the fog drops to obtain a product, the process is simple, and the solution or suspension can be directly prepared into a powder product in a drying tower; by adjusting the prescription and the process parameters, powder particles with the particle size meeting the requirement and good fluidity can be obtained. Therefore, the solid dispersion obtained after spray drying can be directly mixed with other auxiliary materials for tabletting, and the process is simplified. Hot-melt extrusion can treat the high polymer material above the glass transition temperature thereof, so as to promote effective mixing of the thermoplastic adhesive and/or the polymer and the active ingredient at a molecular level; the solid dispersion is prepared without introducing organic solvent or water, the duration of the whole extrusion process is short, and the obtained hot-melt extrusion product can be used in the next process after being simply crushed and sieved and can be directly mixed with other auxiliary materials for tabletting. Compared with the solid dispersion prepared by the powder coating or particle coating process adopted in the patent CN 105142633A, the solid dispersion prepared by the spray drying process or the hot melt extrusion process in the patent has the advantages of simpler process, better taste masking effect and better mouthfeel.
In a first aspect of the present invention, there is provided a donepezil composition comprising a solid dispersion comprising donepezil or a salt thereof, a carrier material.
In a second aspect of the present invention, there is provided a method for preparing a donepezil solid dispersion, which comprises at least one selected from the group consisting of a melting method, a solvent-melting method, a spray-drying method, a milling method and a hot-melt extrusion method.
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
The concentration "ng/mL" refers to nanograms per milliliter, as weight per volume.
mL means mL, L means liter, g means gram, mg means milligram, h means hour, um means micron, mm means millimeter, deg.c means centigrade, rpm means rotation speed, s means second, min means minute.
Yu tex EPO: butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1),
equidch L100-55: methacrylic acid and ethyl acrylate (1:1) copolymer,
HPMCAS: the hydroxypropyl methyl cellulose acetate succinate is added into the mixture,
AUC: area under the drug concentration versus time curve, RH: air relative humidity, XRD: x-ray powder diffraction.
Detailed Description
Based on the deficiencies of the prior art, the present invention has been made through extensive research and study to produce donepezil compositions comprising a solid dispersion comprising donepezil or a salt thereof and a carrier material. The donepezil composition has good taste masking effect and good mouthfeel, and has dissolution property for achieving effective treatment of blood concentration.
In a first aspect of the present invention, there is provided a donepezil composition, the active ingredient being donepezil or a salt thereof, comprising a solid dispersion comprising the active ingredient and a carrier material. In some embodiments, the active ingredient is donepezil; in some embodiments, the active ingredient is donepezil hydrochloride.
The donepezil composition, the carrier material, comprises a methacrylic acid polymer. After the methacrylic acid polymer and the donepezil are prepared into the solid dispersion according to a certain proportion, the solid dispersion has good taste masking effect. In some embodiments, the methacrylic polymer is a methacrylic copolymer. In some embodiments, the methacrylic polymer is a methacrylic acid and ethyl acrylate (1:1) copolymer, having the trade name of EvieQi L100-50.
Ewing L100-55 has dissolution properties that begin to dissolve at pH > 5.5, where human saliva pH is normally neutral, about 6.6 to 7.1, and at which Ewing L100-55 dissolves, adversely affecting taste masking of the drug. However, the invention unexpectedly discovers in the research that the solid dispersion prepared by the Eudragit L100-55 and the donepezil hydrochloride has the advantages that although the solid dispersion of the donepezil is rapidly released in the medium with the pH value of 6.8, the solid dispersion of the donepezil has no obvious bitter taste and numb taste in the oral cavity, and the medicine taste is greatly improved.
The dissolution of the medicine is directly related to the absorption of the medicine in the body, so that the dissolution of the medicine can be inhibited while the effective taste masking is achieved, the adverse effect on the absorption in the body is generated, and the bioavailability is reduced. The Eudragit L100-55 is insoluble in acid medium, the dissolution rate of the prepared product in acid medium is obviously slower than that of the reference preparation sold in the market, and the product with slow dissolution rate generally causes poor absorption and low bioavailability when the medicine passes through the stomach in the acid physiological environment in vivo. However, the results of animal experiments, which are very unexpected by the inventor, show that the technical scheme of the invention has no influence on absorption, has no reduction of bioavailability, and can be equivalent to the commercial reference preparation.
The weight ratio of the active ingredient to the carrier material of the donepezil composition can be 1:3 to 1: 9. In some embodiments, the weight ratio of active ingredient to carrier material is from 1:4 to 1: 7. In some embodiments, the weight ratio of active ingredient to carrier material is from 1:3 to 1:4. In some embodiments, the weight ratio of active ingredient means to carrier material is from 1:3 to 1: 6. In some embodiments, the weight ratio of active ingredient to carrier material is from 1:3 to 1: 7. In some implementations, the weight ratio of active ingredient to carrier material is from 1:4 to 1: 6. In some embodiments, the weight ratio of active ingredient to carrier material is from 1:4 to 1: 9. In some embodiments, the weight ratio of active ingredient to carrier material is from 1:6 to 1: 7; in some embodiments, the weight ratio of active ingredient to carrier material is from 1:6 to 1: 9. In some embodiments, the weight ratio of active ingredient to carrier material is from 1:7 to 1: 9. In some embodiments, the weight ratio of active ingredient to carrier material is 1:3, 1:4, 1:6, 1:7, or 1: 9. The carrier material belongs to a high molecular carrier material, the solvent has certain viscosity, and the weight ratio can ensure that the spray-dried solution has the optimal viscosity range, and the ideal solid dispersion can be obtained only in the optimal viscosity range.
In some embodiments, the donepezil composition, the carrier material is a methacrylic acid and ethyl acrylate (1:1) copolymer, and the weight ratio of active ingredient to methacrylic acid and ethyl acrylate (1:1) copolymer is from 1:3 to 1:9, alternatively from 1:4 to 1: 7.
The donepezil composition, the solid dispersion may further comprise an anti-sticking agent. In some embodiments, the solid dispersion comprises an anti-tack agent.
The anti-sticking agent comprises at least one selected from superfine silica powder, talcum powder, glyceryl monostearate and microcrystalline cellulose. In some embodiments, the anti-sticking agent is selected from aerosil; in some embodiments, talc is selected as the anti-adherent. And the donepezil or the salt thereof and the carrier material are spray-dried, if the antisticking agent is added into the spray solution, the spray-dried product is not easy to agglomerate in a drying cavity and is easy to disperse, and the obtained solid dispersion has better fluidity.
The weight ratio of the anti-sticking agent to the carrier material may be 1:1-1:10, or 1:2-1:5, or 1:3-1: 10. In some embodiments, the weight ratio of antisticking agent to carrier material is 1:3, or 1: 4.5. The anti-sticking agent with the proportion is added for spray drying, and solid dispersion with better fluidity can be obtained.
The donepezil composition, the solid dispersion may further comprise a plasticizer. In some embodiments, the solid dispersion comprises a plasticizer.
The plasticizer comprises at least one selected from poloxamer, propylene glycol, stearic acid, polyethylene glycol, vitamin E polyethylene glycol succinate, triethyl citrate, diethyl phthalate and glycerol monostearate. In some embodiments, the plasticizer is a poloxamer; in some embodiments, the plasticizer is stearic acid; in some embodiments, the plasticizer is polyethylene glycol. The addition of a plasticizer in the hot-melt extrusion process can lower the glass transition temperature of the carrier material.
The weight ratio of the plasticizer to the carrier material may be 1:1-1:10, or 1:4-1:8, or 1:5-1: 10. In some embodiments, the weight ratio of plasticizer to carrier material is 1:4, 1:5, 1:8, or 1: 10.
In some examples, the donepezil composition, the solid dispersion further comprises an anti-tack agent comprising at least one selected from the group consisting of aerosil, talc, glyceryl monostearate and microcrystalline cellulose; the carrier material is methacrylic acid polymer, and the weight ratio of the active component to the methacrylic acid polymer is 1:3-1: 9.
In some examples, the donepezil composition, the solid dispersion further comprising a plasticizer comprising at least one selected from the group consisting of poloxamer, propylene glycol, stearic acid, polyethylene glycol, vitamin E polyethylene glycol succinate, triethyl citrate, diethyl phthalate and glycerol monostearate; the carrier material is methacrylic acid polymer, and the weight ratio of the active component to the methacrylic acid polymer is 1:3-1: 9.
In the donepezil composition, the solid dispersion accounts for 5-80% by weight, or 10-50% by weight. In some embodiments, the weight proportion of the solid dispersion is 10% to 30%; in some embodiments, the solid dispersion is present in a proportion of 30% to 50% by weight. In some embodiments, the weight proportion of the solid dispersion is 12.5%, 19.6%, 24.5%, 37.0% or 40.7%.
The dissolution rate of the donepezil composition in a medium with pH of 6.8 for 15min is more than 85%. In some embodiments, the donepezil composition has a dissolution rate of 91% at 15min in a medium having a pH of 6.8; in some embodiments, the donepezil composition has a dissolution rate of 99% at 15min in a medium having a pH of 6.8.
The donepezil composition of the invention has no bitter taste after staying in the oral cavity of a human for no more than 60 s. In some embodiments, the donepezil composition is placed in the oral cavity without water and timed to begin, the tongue slightly wriggling, rinsed after about 60 seconds, and the taste remaining after rinsing is recorded, with the bitterness assessed as being completely or almost no bitter.
The donepezil composition of the present invention may further comprise at least one selected from the group consisting of a filler, a disintegrant, a lubricant, and a flavoring agent. The filler includes at least one selected from mannitol, microcrystalline cellulose, anhydrous dibasic calcium phosphate, lactose, maltitol, sorbitol, and pregelatinized starch. The disintegrant comprises at least one selected from crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, pregelatinized starch, and corn starch. The lubricant comprises at least one selected from magnesium stearate, sodium fumarate stearate, silica gel micropowder, talcum powder, calcium stearate, polyethylene glycol and hydrogenated vegetable oil. In some embodiments, the donepezil composition further comprises a filler comprising mannitol and microcrystalline cellulose, a disintegrant comprising crospovidone or low-substituted hydroxypropylcellulose, and a lubricant comprising magnesium stearate. In some embodiments, the donepezil composition further comprises a filler which is mannitol and microcrystalline cellulose, a disintegrant which is crospovidone or low-substituted hydroxypropylcellulose, and a lubricant which is magnesium stearate.
The donepezil composition can be prepared into oral administration dosage forms, and the oral administration dosage forms comprise tablets or granules. In some embodiments, the donepezil composition is prepared into a tablet.
In a second aspect of the present invention, there is provided a method for preparing a solid dispersion in a donepezil composition as described above, which comprises at least one of a melting method, a solvent-melting method, a spray-drying method, a milling method and a hot-melt extrusion method.
In some embodiments, the method for preparing the solid dispersion in the donepezil composition is a spray drying method, comprising the steps of:
(1) dispersing active ingredients, carrier materials and/or an anti-sticking agent in a solvent, and uniformly stirring to obtain a solution or a suspension;
(2) and (3) carrying out spray drying on the solution or suspension obtained in the step (1) to obtain the donepezil solid dispersion.
The donepezil solid dispersion prepared by the spray drying method has small particle size, and does not generate gritty feeling after being prepared into orally disintegrating tablets. Spray drying is a drying method which adopts an atomizer to disperse raw material liquid into fog drops and uses hot gas (air, nitrogen or superheated steam) to dry the fog drops to obtain a product, the process is simple, the solution or suspension can be directly prepared into a powder product in a drying tower, and powder particles with the particle size meeting the requirement and better fluidity can be obtained by adjusting the prescription and process parameters. Therefore, the solid dispersion obtained after spray drying can be directly mixed with other auxiliary materials for tabletting, and the process is simplified.
In some embodiments, the method of preparing the solid dispersion in the donepezil composition is a hot-melt extrusion method comprising the steps of:
and (3) carrying out hot-melt extrusion on the mixture of the active ingredient, the carrier material and/or the plasticizer, and crushing and sieving the hot-melt extrusion product to obtain the donepezil solid dispersion.
The solid dispersion prepared by the hot-melt extrusion method can also obtain smaller particles through crushing and sieving, can be prepared into orally disintegrating tablets, does not generate gritty feeling, and does not bring extra bitterness due to crushing and damaging the particles. Hot-melt extrusion can treat the high polymer material above the glass transition temperature thereof, so as to promote effective mixing of the thermoplastic adhesive and/or the polymer and the active ingredient at a molecular level; the solid dispersion is prepared without introducing organic solvent or water, the duration of the whole extrusion process is short, and the obtained hot-melt extrusion product can be used in the next process after being simply crushed and sieved and can be directly mixed with other auxiliary materials for tabletting.
The preparation method of the donepezil solid dispersion provided by the invention is simple and easy to implement, has good reproducibility and is suitable for industrial production.
Drawings
FIG. 1 is an XRD (X-ray powder diffraction) pattern of donepezil hydrochloride as a raw material drug.
Fig. 2 is an XRD pattern of the solid dispersion (hot-melt particles 4) in the example.
Fig. 3 is an XRD pattern of the mixture obtained by weighing donepezil hydrochloride, ewchic L100-55, and polyethylene glycol in the same proportion as the hot-melt particles 4 in the example, without preparing a solid dispersion, and directly mixing.
Fig. 4 is an XRD pattern of the solid dispersion (spray dried particles 1) in the example.
FIG. 5 is an XRD pattern of a mixture obtained by weighing donepezil hydrochloride, Ewing L100-55 and aerosil in the same proportion as that of spray-dried particles 1, directly mixing without preparing a solid dispersion in the example.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the following examples, the components in the formulation are in percent by weight.
In the following examples, donepezil hydrochloride, a crude drug, is used as a crystal, and its XRD pattern is shown in fig. 1.
In the following examples, the conditions of the hot-melt extrusion method and the spray drying method were as follows:
hot melt extrusion method instrument: twin screw extruder, american siemer feishol Process 11.
Spray drying apparatus: spray drier, Swiss Tachi B-290.
Hot melt granule preparation
TABLE 1 preparation of donepezil hydrochloride and Eiteqi L100-55 hot-melt granules in different proportions
Figure BDA0002957441050000081
The preparation method comprises the following steps: mixing donepezil hydrochloride, Eudragit L100-55 and plasticizer for 10min, adding into hot melt extrusion equipment, performing hot melt extrusion according to a set temperature to obtain a strip-shaped extrudate, and crushing and sieving the strip-shaped extrudate by using a crusher to obtain hot melt granules.
The XRD pattern of the hot melt granules 4 is shown in figure 2; donepezil hydrochloride, Equidi L100-55, and polyethylene glycol were weighed in the same proportion as the hot-melt particles 4, and were directly mixed without preparing a solid dispersion, and the XRD pattern of the resulting mixture was shown in FIG. 3.
Spray-dried granular preparation
TABLE 2 preparation of spray-dried particles of donepezil hydrochloride and Eiteqi L100-55 in different proportions
Figure BDA0002957441050000082
The preparation method comprises the following steps: dissolving donepezil hydrochloride and Eudragit L100-55 into acetone-ethanol-water (45:45:10, weight ratio), adding dispersant under stirring, dispersing uniformly, homogenizing with homogenizer before spray drying, and spray drying with spray drying equipment to obtain spray dried granule.
The XRD pattern of spray dried granule 1 is shown in FIG. 4; donepezil hydrochloride, Eudragit L100-55 and aerosil are weighed according to the same proportion of the spray-dried particles 1, and are not prepared into solid dispersion, and are directly mixed, and the XRD pattern of the obtained mixture is shown in figure 5.
Example 1
The preparation method comprises the following steps: mixing hot melt granule 1 with sucralose, essence, low-substituted hydroxypropyl cellulose, and crospovidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 2
The preparation method comprises the following steps: mixing hot melt granule 2 with aspartame, essence, low-substituted hydroxypropyl cellulose, and crospovidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 3
The preparation method comprises the following steps: mixing hot melt granule 3 with sucralose, essence, and polyvinylpolypyrrolidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 4
The preparation method comprises the following steps: mixing hot melt granule 4 with sucralose, essence, and polyvinylpolypyrrolidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 5
The preparation method comprises the following steps: mixing hot melt granule 5 with sucralose, essence, low-substituted hydroxypropyl cellulose, and crospovidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 6
The preparation method comprises the following steps: mixing spray-dried granule 1 with microcrystalline cellulose and polyvinylpolypyrrolidone for 5min, adding sucralose, essence and mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 7
The preparation method comprises the following steps: mixing spray-dried granule 2 with silicified microcrystalline cellulose and crospovidone for 5min, adding sucralose, essence, low-substituted hydroxypropyl cellulose and mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 8
The preparation method comprises the following steps: mixing spray-dried granule 3 with silicified microcrystalline cellulose and crospovidone for 5min, adding sucralose, essence, low-substituted hydroxypropyl cellulose and mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
TABLE 3 different Hot melt granulates were prepared as tablets
Figure BDA0002957441050000091
Figure BDA0002957441050000101
TABLE 4 different spray-dried granules prepared into tablets
Prescription composition Example 6 proportion (%) Example 7 proportion (%) Example 8 proportion (%)
Spray-dried granules 1 20.83 / /
Spray-dried granules 2 / 30.00 /
Spray-dried granules 3 / / 30.00
Mannitol 30.67 21.30 20.50
Microcrystalline cellulose 25.00 / /
Silicified microcrystalline cellulose / 25.00 25.00
Cross-linked polyvidone 20.00 15.00 15.00
Low-substituted hydroxypropyl cellulose / 5.00 5.00
Sucralose 2.00 2.20 2.50
Essence 0.50 0.50 1.00
Magnesium stearate 1.00 1.00 1.00
Total of 100.00 100.00 100.00
Comparative example 1: (direct addition of flavoring agent)
Orally disintegrating tablets were prepared by direct addition of a corrigent, the prescription information being shown in Table 5
TABLE 5 comparative example 1 information Table
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 4.17
Mannitol 66.33
Microcrystalline cellulose 15.00
Cross-linked polyvidone 10.00
Saccharin sodium salt 1.00
Sucralose 2.00
Essence 0.50
Magnesium stearate 1.00
Total up to 100.00
The preparation method comprises the following steps: mixing donepezil hydrochloride with essence, saccharin sodium, sucralose, crospovidone, and microcrystalline cellulose for 10min, adding mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 2: (Cyclodextrin Inclusion)
The oral disintegrating tablets are prepared by cyclodextrin inclusion, and the prescription information is shown in Table 6
Table 6 comparative example 2 information table
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 4.17
Hydroxypropyl cyclodextrins 41.67
Mannitol 27.16
Microcrystalline cellulose 15.00
Cross-linked polyvidone 10.00
Sucralose 1.00
Magnesium stearate 1.00
Total of 100.00
The preparation method comprises the following steps: weighing hydroxypropyl cyclodextrin, dissolving in purified water, adding donepezil hydrochloride into cyclodextrin water solution under stirring, freeze drying the solution, sieving with 40 mesh sieve, mixing with sucralose, mannitol, microcrystalline cellulose and crospovidone for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 3 (ion exchange resin)
Preparation of orally disintegrating tablets by ion exchange resin, prescription information is shown in Table 7
TABLE 7 comparative example 3 information Table
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 4.17
Polacrilin potassium 6.25
Microcrystalline cellulose 20.00
Mannitol 56.58
Cross-linked polyvidone 10.00
Sucralose 1.50
Essence 0.50
Magnesium stearate 1.00
Total of 100.00
The preparation method comprises the following steps: dissolving donepezil hydrochloride into 100ml of purified water, adding potassium polacrilin, stirring and exchanging for 4h, filtering and washing, repeating for 3 times, taking a resin compound, drying at 45 ℃ in a drying oven to obtain a dried drug-resin compound, adding microcrystalline cellulose, crospovidone, sucralose and essence, mixing for 10min, adding mannitol, mixing for 10min, and finally adding magnesium stearate, and mixing for 5 min.
Comparative example 4: (according to literature with the Ettqi EPO spray-dried)
Table 8 prescription information table for comparative example 4
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 4.17
Ewing EPO 29.19
Talcum powder 7.29
Mannitol 20.85
Microcrystalline cellulose 20.00
Cross-linked polyvidone 15.00
Sucralose 2.00
Essence 0.50
Magnesium stearate 1.00
Total up to 100.00
The preparation method comprises the following steps: dissolving the Esterqi EPO in 95% ethanol, adding the donepezil hydrochloride and the talcum powder in sequence, stirring and dispersing, and then homogenizing and dispersing by a homogenizer to obtain a spray-dried solution. And (4) spraying the solution by using a spraying device to obtain a sprayed object. Mixing the spray-dried product with sucralose, essence, and polyvinylpolypyrrolidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 5: (according to literature using the unique EPO hot melt)
TABLE 9 prescription information Table for comparative example 5
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 4.17
Ewing EPO 20.83
Polyethylene glycol 6000 2.18
Mannitol 39.32
Microcrystalline cellulose 20.00
Cross-linked polyvidone 10.00
Sucralose 2.00
Essence 0.50
Magnesium stearate 1.00
Total up to 100.00
The preparation method comprises the following steps: mixing donepezil hydrochloride with Uttqi EPO and polyethylene glycol 6000 for 10min, adding into hot melt extrusion equipment, hot melt extruding at 140 ℃ to obtain strip-shaped extrudate, and crushing the strip-shaped extrudate by a crusher and sieving with a 100-mesh sieve to obtain hot melt granules. Mixing the hot melt granules with sucralose, essence and crospovidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 6: (other materials HPMCAS-LF Hot melt)
TABLE 10 prescription information Table for comparative example 6
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 4.17
HPMCAS-LF 16.67
Poloxamer P188 2.84
Mannitol 42.82
Microcrystalline cellulose 20.00
Cross-linked polyvidone 10.00
Sucralose 2.00
Orange essence 0.50
Magnesium stearate 1.00
Total up to 100.00
The preparation method comprises the following steps: mixing donepezil hydrochloride, HPMCAS-LF and poloxamer P188 for 10min, adding into a hot-melt extrusion device, carrying out hot-melt extrusion at 160 ℃ to obtain a strip-shaped extrudate, and crushing the strip-shaped extrudate by using a crusher and sieving the crushed extrudate with a 100-mesh sieve to obtain hot-melt granules. Mixing the hot melt granules with sucralose, essence and crospovidone for 10min, adding mannitol and microcrystalline cellulose, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 7 (example 26 in CN 101090737: Eiteqi L100-55 and active ingredient Wet granulation)
TABLE 11 prescription information Table for comparative example 7
Prescription composition Prescription ratio (%)
Donepezil hydrochloride 7.00
Ethyl cellulose 24.00
Youteqi L100-55 22.00
Lactose 44.20
Low-substituted hydroxypropyl cellulose 2.50
Magnesium stearate 0.30
Total of 100.00
The preparation method comprises the following steps: mixing donepezil hydrochloride, Eudragit L100-55, lactose, and ethyl cellulose for 5min, dissolving low-substituted hydroxypropyl cellulose in appropriate amount of purified water, adding into the above mixture, granulating, drying wet granules, sieving with 30 mesh sieve, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 8:
commercially available donepezil hydrochloride orally disintegrating tablets
The result of the detection
The samples were individually evaluated for taste masking by electronic tongue, and 10 additional volunteers were recruited for oral evaluation.
1: electronic tongue taste masking detection
An experimental instrument: taste analysis system by INSENT, Japan, model number: TS-5000Z; sensor AN0(B-bitterness 2)
Reagents for experiments: reference solution (near tasteless): 30mM KCl +0.3mM tartaric acid; negative electrode cleaning solution: water + ethanol + HCl;
positive electrode cleaning solution: KCl + water + ethanol + KOH
The sample processing method comprises the following steps: dissolving donepezil hydrochloride raw material medicine into 10mM KCl to prepare 1mg/g solution as positive control, wherein the bitterness value of the solution is 100%; taking 3 tablets of different embodiments, respectively putting the tablets into a beaker filled with 160ml of warm water (37 ℃) and stirring the tablets for 60 seconds by a magnetic stirrer, and then filtering the sample to obtain a supernatant for testing; the measurement flow is shown in FIG. 1.
And (3) measuring results:
TABLE 12 electronic tongue bitterness test results
Figure BDA0002957441050000141
Figure BDA0002957441050000151
The bitterness value of the raw material medicine is 100%, the larger the value is, the larger the bitterness is, the smaller the value is, and the smaller the bitterness is. From the table, the difference of the bitter taste of various examples is large, wherein the bitter taste values of the tablets of examples 2, 4, 5,6, 8 and comparative example 3 are obviously smaller than those of the bulk drug, the difference is obvious, which shows that the bitter taste is obviously reduced and the taste masking effect is obvious; although the bitter taste value of the example 1 is greatly reduced compared with that of the bulk drug, the bitter taste value is more than 50%, and the taste masking effect is not ideal enough; the comparative examples 1, 2, 4 to 8 have a large bitterness, which indicates that the bitterness is still large and the taste masking effect is poor.
The electronic tongue result shows that the invention has good taste masking effect, can obviously mask bitter taste, and has obvious advantages compared with the commercially available donepezil hydrochloride orally disintegrating tablets. The product prepared from polacrilin potassium ion resin also shows better taste masking effect, and we continue to evaluate the product.
2: evaluation of volunteers by oral test
Sample testing method: the volunteers rinsed 2 times with 30ml of purified water, and then placed the sample on the tongue, moistened with saliva and lightly pressed with the tongue for 60s, and then made a head-up movement once (for 30 s) during the period, so that the bitter taste of the drug can be felt in the bitter taste-sensitive areas of the root and side of the tongue. Spit out after 60s, rinse 5 times until no bitterness in the mouth, and measure another sample after 30 min.
Evaluation criteria: the bitterness of the volunteers was scored according to the following criteria based on the results of oral tasting, and the score of each example was averaged over 10 volunteers.
TABLE 13 taste evaluation Standard
Figure BDA0002957441050000152
TABLE 1410 average results of oral test evaluations on volunteers
Figure BDA0002957441050000161
The taste test results of volunteers show that the scores of examples 2, 3, 5,6 and 8 are higher, which shows that the masking effect on bitter taste and numb taste is ideal, the taste is obviously improved compared with the taste of the commercial preparation, and particularly when the proportion of the Eudragit L100-55 is increased, the bitter taste and the numb taste can be completely masked; the ratio of the active ingredient and the Eudragit L100-55 is maximally considered to be 1:9, which is enough for well taste masking, if the dosage of the L100-55 is increased, the difficulty of the preparation forming is increased, and if the dosage of the Eudragit L100-55 is too much, the material is wasted, and the excessive auxiliary material taste is brought, so the active ingredient of the invention: the upper limit of the ratio of Uttky L100-55 is limited to 1: 9.
In the embodiment 1, the proportion of the Eudragit L100-55 is low, so that the covering effect is obvious and not ideal; the product prepared by the polacrilin potassium ion resin in the comparative example 3 also shows better taste masking effect, the bitterness and the numbing taste are weaker, and the taste result of the volunteers is consistent with the evaluation result of the electronic tongue.
3: dissolution testing
After the medicine is orally taken, the medicine firstly enters the stomach, most of the medicine begins to disintegrate and release in the stomach, and the release is the premise of absorption, so 0.1N HCl is selected as one of evaluation media; the major absorption portion of the drug was the small intestine, which was basic, so medium ph6.8 was chosen as the additional medium for evaluation. The dissolution test was performed on examples 3 and 8 and comparative examples 3 and 8 by the following method, and the amount of dissolution was compared between each example and comparative example.
TABLE 15 dissolution results of examples 3, 8 and comparative examples 3, 8 in 0.1N HCl medium
Sample (I) 5min 10min 15min 20min 30min 45min 60min
Example 3 18±1.53 32±1.00 42±0.58 50±1.15 60±1.53 71±1.00 76±2.08
Example 8 31±0.58 47±1.00 56±1.53 61±2.08 69±2.08 77±2.08 82±2.08
Comparative example 3 76±2.00 82±1.00 85±1.00 86±1.15 89±1.00 91±1.00 91±1.00
Comparative example 8 73±4.32 94±4.32 99±2.79 100±1.67 103±4.50 101±1.51 101±1.03
Due to the dissolution characteristics of Eiteqi L100-55, the dissolution of inventive examples 3 and 8 under acidic conditions is significantly slower than that of the commercial reference, while the orally disintegrating tablets prepared from comparative 3 Polacrillin Potassium ion resin have significantly higher similarity to the reference of comparative 8 in hydrochloric acid medium, indicating that the amount of drug released in acidic medium is less than that of the ionic resin and the reference, and that if the present invention reaches but the small intestine is not yet completely released, the drug absorption is likely to be affected.
TABLE 16 dissolution results of examples 3 and 8 and comparative examples 3 and 8 in pH6.8 medium
Sample (I) 5min 10min 15min 20min 30min 45min 60min
Example 3 60±3.61 87±1.53 99±0.58 100±0.58 102±0.58 102±0.00 102±1.53
Example 8 69±2.65 84±4.51 91±2.08 94±2.83 101±3.06 102±1.15 103±1.00
Comparative example 3 65±1.15 73±1.53 73±1.53 80±0.58 81±0.58 84±0.58 85±0.58
Comparative example 8 79±2.00 99±1.53 99±1.53 99±1.53 99±1.53 99±2.08 99±1.53
The dissolution results show that the commercial reference preparations of examples 3 and 8 and comparative example 8 of the invention are all rapidly dissolved in a medium with pH6.8, the dissolution rate is more than 85% in 15min, and the dissolution is similar. The invention has no influence on dissolution in pH6.8, and has better mouthfeel than a reference. Compared with the product prepared by the Poland Crin potassium ion resin in the comparative example 3, the dissolution rate of the product in the medium with the pH value of 6.8 is slow, only about 85% of the product can be released, and the platform is low.
4: bioavailability evaluation
The results of in vivo bioavailability studies using cynomolgus monkeys comparing the pharmacokinetic data of example 2, comparative example 3 and a commercially available reference are shown in the table
Table 17 example 2 and comparative example 3 pharmacokinetic results in vivo with a commercially available reference (n ═ 7)
Figure BDA0002957441050000171
In vivo pharmacokinetic data indicate that the AUC (area under the drug concentration and time curve) of the invention is close to that of a commercial reference, and Ratio (%) is in the range of 80.00-125.00% of the reference preparation, namely that the two preparations are bioequivalent in cynomolgus monkeys and have the same curative effect. While the AUC of the ion resin is lower, the Ratio (%) is only 76.75% of that of the reference preparation, which indicates that the absorption is incomplete and the bioavailability is reduced.
Although the product prepared by compounding the ion exchange resin can achieve the similar taste masking effect as the product prepared by compounding the ion exchange resin, the product is obviously poorer in vivo absorption, the analysis reason is probably that the drug is incompletely released at the small intestine part, so that the absorption is insufficient, and the problem is also laterally fed back when the in vitro pH6.8 dissolution platform is lower.
Therefore, the invention can normally exert the curative effect of the medicament without influencing the absorption of the medicament in the body under the condition that partial medium dissolution is inhibited, and has excellent mouthfeel.
5: stability quality assessment
The inventive example 3 was double-aluminum packaged, and the related substances were examined for 6 months and 6 months accelerated, and the results were as follows:
TABLE 18 stability results
Figure BDA0002957441050000172
The stability test results show that the product prepared in the example 3 of the invention is stored for 6 months under long-term and accelerated conditions, the related substances are not increased, and the quality is stable.
The 5 results are combined to show that the product obtained by the technology of the invention does not affect the curative effect of the medicine while masking the taste, has excellent quality, has obvious advantages compared with the products sold in the market, and has important significance for improving the medicine taste of patients, increasing the medicine taking compliance and improving the life quality of the patients.
In the description of the present specification, reference to the terms "some embodiments," "one specific example," or "some examples," etc., means 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 present invention. In this specification, the schematic representations of the terms used above are not necessarily intended to 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. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (14)

1. A donepezil composition, the active ingredient being donepezil or a salt thereof, comprising a solid dispersion comprising said active ingredient and a carrier material.
2. The donepezil composition according to claim 1, said carrier material comprising a methacrylic acid polymer.
3. Donepezil composition according to claim 1 or 2, the weight ratio of the active ingredient to the carrier material being from 1:3 to 1: 9.
4. Donepezil composition according to any of claims 1 to 3, said carrier material being a methacrylic acid and ethyl acrylate (1:1) copolymer, the weight ratio of said active ingredient to said methacrylic acid and ethyl acrylate (1:1) copolymer being from 1:3 to 1: 9.
5. The donepezil composition according to any one of claims 1 to 4, said solid dispersion further comprising an antisticking agent or a plasticizer.
6. The donepezil composition according to claim 5, wherein said antisticking agent comprises at least one selected from the group consisting of aerosil, talc, glyceryl monostearate and microcrystalline cellulose.
7. The donepezil composition according to claim 5, said plasticizer comprising at least one selected from the group consisting of poloxamer, stearic acid, polyethylene glycol, propylene glycol, vitamin E polyethylene glycol succinate, triethyl citrate, diethyl phthalate and glycerol monostearate.
8. The donepezil composition according to claim 1, said solid dispersion further comprising an anti-tack agent comprising at least one selected from the group consisting of aerosil, talc, glyceryl monostearate and microcrystalline cellulose; the carrier material is methacrylic acid polymer, and the weight ratio of the active component to the methacrylic acid polymer is 1:3-1: 9.
9. The donepezil composition according to claim 1, said solid dispersion further comprising a plasticizer comprising at least one selected from the group consisting of poloxamer, propylene glycol, stearic acid, polyethylene glycol, vitamin E polyethylene glycol succinate, triethyl citrate, diethyl phthalate and glycerol monostearate; the carrier material is methacrylic acid polymer, and the weight ratio of the active component to the methacrylic acid polymer is 1:3-1: 9.
10. Donepezil composition according to any of claims 1 to 9, having a dissolution rate of more than 85% in a medium having a pH of 6.8 for 15 min.
11. Donepezil composition according to any of claims 1 to 10, which further comprises at least one member selected from the group consisting of fillers, disintegrants, lubricants and flavouring agents; the filler comprises at least one selected from mannitol, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, lactose, maltitol, sorbitol and pregelatinized starch; the disintegrant comprises at least one selected from crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, pregelatinized starch and corn starch; the lubricant comprises at least one selected from magnesium stearate, sodium fumarate stearate, silica gel micropowder, talcum powder, calcium stearate, polyethylene glycol and hydrogenated vegetable oil.
12. Donepezil composition according to any of claims 1 to 11, characterized in that the solid dispersion is prepared by a process comprising at least one selected from the group consisting of a melt process, a solvent-melt process, a spray-drying process, a milling process and a hot-melt extrusion process.
13. The donepezil composition according to claim 12, said spray drying process comprising the steps of:
(1) dispersing active ingredients, carrier materials and/or an anti-sticking agent in a solvent, and uniformly stirring to obtain a solution or a suspension;
(2) and (3) carrying out spray drying on the solution or suspension obtained in the step (1) to obtain the donepezil solid dispersion.
14. The donepezil composition according to claim 12, said hot-melt extrusion process comprising:
and (3) carrying out hot-melt extrusion on the mixture of the active ingredient, the carrier material and/or the plasticizer, and crushing and sieving the hot-melt extrusion product to obtain the donepezil solid dispersion.
CN202110229791.5A 2020-03-04 2021-03-02 Composition of acetylcholinesterase inhibitor and preparation method thereof Pending CN113350291A (en)

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