CN101596197B - Quick-release medicinal composition and preparation method thereof - Google Patents

Abstract

The present invention relates to a quick-release medicinal composition, which contains indiplon and pharmaceutically acceptable carrier. The oral quick-release composition prepared from the indiplon and the quick-release carrier can provide a new convenient medicament administration mode and a new dosage form for oral medicaments under the special conditions that the medicaments are difficult to swallow and inconvenient to drink water. Compared with a common oral preparation, because the mucosa of the gastrointestinal tract is widely covered by rapidly-disintegrated medicament, the medicinal composition has quick response. If the medicament can be absorbed through the mucosa of the oral cavity, the medicinal composition has no first-pass effect so as to improve the bioavailability and reduce the stimulation to the stomach and intestine.

Description

Quick-release medicinal composition and preparation method thereof

Technical field

The present invention relates to a kind of rapid-release vehicle and sedative hypnotic drug composition and method of making the same, quick-release medicinal composition of the present invention is made up of active constituents of medicine indene and pharmaceutically acceptable carrier with rapid release function.Be mainly used in the sleep disorder that tranquilizing soporific and a variety of causes cause.

Background technology

" insomnia " is meant that the patient does not have enough sleep or feels all relevant uncomfortable states with sleep.The insomnia is a kind of common disease.The most direct consequence of insomnia causes the metabolic disorder of human body exactly, reduces production efficiency, causes that emotion, behavior and psychomotor function aspects change; Insomnia and some other disease association comprise the obstacle of depression, anxiety neurosis, gastrointestinal tract and cardiovascular system etc. in addition.Last century, the long run test of the nineties Chicago University proved absolutely this point: the crowd of reception test, only allow to sleep 4 hours every night, and the test period span is 6 days.Found that their endocrine ability and the respond of insulin descended 30% respectively, and the reduction significantly of these indexs, the early stage sign of diabetes often.Other has report, and long-term insomniac's serious contingency and wound incidence rate are obviously than normal person height.It is reported, the survey showed that for of carrying out in the adult of Los Angeles, in survey scope, there is 32% adult to suffer from the insomnia approximately, the result that same investigation is carried out Florida Alachua prefecture is at least 45% suffered from sleeping by investigation adult population report or keep the sleep state difficulty, in the investigated population in gondola San Marino, there is 13% crowd to suffer from the insomnia approximately.The data of WHO shows that the whole world has nearly 1/4 people to be subjected to the insomnia puzzlement.The insomnia is relevant with individual age and sex, and sickness rate is than higher in more old individuality and women.Insomnia is a very general problem in China, and Epidemiological study shows that adult insomnia's sickness rate is 30～35%, and is particularly in the majority with women and old man.The survey data of Chinese Medical Association shows that China's sleep disorder prevalence reaches 42.7%, has 300,000,000 middle age to suffer from sleep disorder approximately.

Insomnia is dealt with improperly, is a medical care problem, also is a social problem.On the traditional sense, insomnia's processing is comprised the treatment and the alleviation of etiology factor, improve sleep quality and use sleeping pill.At present, insomnia's treatment means is mainly taked two kinds of Drug therapy and non-drug therapies: the First Principles of non-drug therapy is " Sleep hygiene " (sleep hygiene), and this insomnia that a variety of causes is caused all is necessary; When Sleep hygiene and non-drug therapy were invalid when having a sleepless night serious, Drug therapy just became first-selection.

At present the clinical insomnia's of being used for the treatment of medicine mainly contains barbital and non-barbiturates, benzene phenodiazine Class, antihistaminic, antipsychotic drug and other tranquilizer, wherein benzene phenodiazine Class is most widely used.The benzene phenodiazine

The class drug main will by with GABA (γ-An Jidingsuan) receptors bind, regulate the release of inhibitory nerve mediator GABA, weaken neuronic activity and play a role.But simultaneously because the benzene phenodiazine

The class medicine to the GABA receptor subtype in conjunction with lacking selectivity, thereby often cause the generation of untoward reaction, as dysmnesia, next day still residual sedation, the place phenomenon etc. of sleeping being arranged.Therefore, develop that a kind of determined curative effect, untoward reaction are light, the medicine of quick acting has seemed very necessary.

In being used for the treatment of insomnia's patent drug, first non-benzene phenodiazine The patent of the market leader Ambien of class medicine-present expired in 2007, and this will provide a huge market opportunity for the brand medicine of new generation after the improvement.Second non-benzene phenodiazine

The class medicine is Zaleplon (Zaleplon).The 3rd non-benzene phenodiazine

Promptly by the indene (indiplon) of the common exploitation of Pfizer and Neurocrine company, as a kind of novel Pyrazolopyrimidines type medicine, optionally with the effect of GABAA receptor alpha 1 hypotype, this species specificity is in conjunction with reducing the benzene phenodiazine for the class medicine

The generation of the untoward reaction that the class medicine is had.Indene is as the non-benzene phenodiazine of developing recently

Class is the sedative hypnotic safely and effectively, and is rapid-action, and action time is short, do not have the effect of obviously being still drank after a night, knock-on aypnia and withdrawal symptom, evident in efficacy and better tolerance, and action time is of short duration to make also correspondingly minimizing of untoward reaction, is insomniac's Gospel.Indene may become the goldstandard (Gold standard) of sleep medicine.At present, indene has been finished III phase clinical research experiment, estimates and will at first go on the market in the U.S. in the near future.

At present, Chang Gui pharmaceutical dosage form is ejection preparation or oral formulations.For oral formulations, need water to swallow usually.Because the particularity of war, army's objective natural environment in residing wartime is comparatively special even abominable, because of hydropenia makes the medicine difficulty of swallowing; For the wounded or the patient of dysphagia, then can not as the normal person, take medicine.Therefore, the administering mode of using medicine under some specific conditions is satisfied in research, and especially quick, convenient and rapid-action administering mode is of crucial importance.

Oral cavity disintegration tablet is a kind of new oral solid preparation of occurring of medical market abroad in recent years.In May, 2002 Bureau of Drugs Supervision of country " meeting summary of relevant fast-release tablet, oral instant-dissolving tablet and oral cavity disintegration tablet " points out: the characteristics of this dosage form are: " do not need water or need low amounts of water; also need not to chew; medicine places lingual surface, after the disintegrate, borrow swallowing act to go into the stomach onset rapidly." U.S. food Drug Administration (FDA) regarded as a kind of new dosage form in 1998 with oral cavity disintegration tablet, be defined as: " a kind of solid dosage forms that contains therapeutic component, when placing lingual surface, can disintegrate rapidly in the several seconds ".

The advantage of oral cavity rapid release pharmaceutical composition: for novel form has been opened up in emergent treatment, injection type is mainly taked in first aid at present, but drug administration by injection all needs certain device and professional, this just might incur loss through delay patient's treatment, and the oral cavity rapid release pharmaceutical composition is that the treatment of some emergency cases (as shock, hypertension, vomiting, pain, epilepsy etc.) provides new approach; Compare with common oral preparation, extensively covered by the medicine of speed after collapsing because of gastrointestinal tract mucous, onset is rapid, if medicine can absorb by the through port transmucosal, has removed first pass effect from, has caught high bioavailability, and minimizing is to gastrointestinal irritation; For particular patients ' provides a kind of new dosage form that makes things convenient for, because oral cavity disintegration tablet does not need in mouth under water can obey, therefore brought Gospel for old man, child, bed and the bad patient of function of deglutition, also catch and supplied convenience, therefore in oral administration system, have special advantages for people's oral medication of drinking-water inconvenience; To drinking water inconvenience or because of the patient of injured dysphagia and the special circumstances such as people in plateau, desert area and ocean, taking of oral cavity disintegration tablet is very convenient, therefore, this new form of administration of oral cavity disintegration tablet can be taken at any time, and onset is rapid, and is with the obvious advantage.

Current, the preparation technology of external oral cavity disintegration tablet is comparatively ripe, and begins to be applied in the Western medicine preparation industry, has nearly 30 kinds of preparations to come into the market, is subjected to the patient and welcomes.In international markets such as the U.S., Japan, the product of list marketing has respiratory system, antiallergic action, blood circulation, digestive system and spiritual class medicine.World's rapidly disintegrating formulation sales volume reached 200,000,000 dollars in 1996, and the retail sales of 1 product of Claritin loratadine speed disintegrating tablet in 2000 has reached 2.98 hundred million dollars.Desloratadine oral cavity disintegration tablet listing in 2005 is applied to child and elderly patients.At present, the market scale of oral rapidly disintegrating product is near 1,000,000,000 yuan of dollars, and rate of increase surpasses 40%.

The preparation method of oral cavity disintegration tablet mainly comprises freeze-drying and pressed disc method, and wherein, lyophilization is used the earliest, Technology maturation, but complicated operation, and the production cycle is long, and the cost height is used more abroad.The tabletting rule adopts the filler water miscible, that granularity is less, and adding has the humectant that draws of powerful imbibition effect in preparation, so that make moisture content can enter tablet inside fast, make tablet disintegrate rapidly at short notice, this method technology is simple, and production cost is low, but technical difficulty is big; Abroad in this respect the application of pressed disc method aspect multiple patented technology, as particulate carrier tabletting (medicine-feeding technology is released in sudden strain of a muscle), premixing tabletting (microcapsule technique for packing) etc.

Summary of the invention

The objective of the invention is provides a kind of quick-release medicinal composition for insomnia or treatment of sleep disorders.It comprises active constituents of medicine indene and pharmaceutically acceptable carrier, and indene has the structure of formula (I):

Formula (I).

In the preferred embodiments of the present invention, the mass percent that described indene accounts for quick-release medicinal composition is 1-20%.

In the preferred embodiments of the present invention, above-mentioned pharmaceutically acceptable carrier comprises cross-linking sodium carboxymethyl cellulose (CCNa), polyvinylpolypyrrolidone (PVPP XL), micropowder silica gel (SiO ₂) or magnesium stearate.Pharmaceutically acceptable carrier can also comprise filler or correctives.

Wherein, above-mentioned filler is selected from one or more in microcrystalline Cellulose (MCC), pregelatinized Starch (Starch), mannitol, lactose, dextrin, the starch.

Above-mentioned correctives is selected from one or more in Rhizoma et radix valerianae, Fructus Pruni pseudocerasi, Fructus Vitis viniferae, Fructus Fragariae Ananssae, Fructus Citri tangerinae, Fructus Mali pumilae, citric acid, Herba Menthae, Fructus Musae, Fructus Ananadis comosi, honey peach essence, maltose alcohol, saccharin sodium, protein sugar, sucrose, vanillin, Mentholum, aspartame, the stevioside, be preferably vanillin, citric acid and aspartame.

The optimization formula of quick-release medicinal composition of the present invention consists of (percentage by weight):

Indene 1-20%

Cross-linking sodium carboxymethyl cellulose 2-15%

Polyvinylpolypyrrolidone 2-20%

Micropowder silica gel 0.5-3%

Surplus is magnesium stearate, filler and correctives.

More preferably, above-mentioned quick-release medicinal composition prescription consists of (percentage by weight):

Indene 2-5%

Cross-linking sodium carboxymethyl cellulose 8%

Polyvinylpolypyrrolidone 10%

Micropowder silica gel 1%

Magnesium stearate 0.1%

Surplus is filler and correctives.

The present invention also provides the preparation method of above-mentioned quick-release medicinal composition, it mainly comprises step: after indene and pharmaceutically acceptable carrier are sieved respectively, progressively increase by equivalent and to add the magnesium stearate mixing again behind the mixing, adopt tabletting to prepare sheet and heavily be 100-500mg, hardness is the tablet of 30N～80N, promptly gets quick-release medicinal composition.

Quick-release medicinal composition of the present invention can be used for preparing the medicine for the treatment of sleep disorder.

Above active constituents of medicine (indene) is synthesized into voluntarily by the inventor, can also obtain by purchase, as long as meet pharmaceutical standards, can use.

The present invention invention is prepared into the oral cavity rapid release compositions with indene and rapid-release vehicle, can provide new administering mode and the novel form of making things convenient for for some dysphagias or the inconvenient oral medication in particular cases of drinking-water.Compare with common oral preparation, extensively covered by the medicine after fast the collapsing because of gastrointestinal tract mucous, onset is rapid, if medicine can absorb by the through port transmucosal, no first pass effect has improved bioavailability, reduces gastrointestinal irritation.

The specific embodiment

The inventor has carried out screening experiment, obtains optimization formula of the present invention, below is screening process:

(1) prescription trial-production

1 instrument and reagent

(1) instrument:

JAL2003A type electronic balance, the sub-instrument plant of last Nereid's atmospheric electricity;

The TDP-1.5T single punch tablet machine, Shanghai hat connection drugs manufacture equipment company limited, punch die 12mm; SG-IIB-6 type thermostat water bath, Shanghai instrument (group) supply and marketing company limited;

78X-3A matrix agent four-function analyzer, Shanghai Huanghai Sea medicine inspection Instr Ltd.;

ZP-19 type rotary tablet machine, the Shanghai first pharmaceutical machine factory.

(2) reagent

Indene meets the pharmaceutical quality standard.Content 〉=99.0%;

Low-substituted hydroxypropyl cellulose (L-HPC), pharmaceutical grade, Huzhou Zhanwang Pharmaceutical Co., Ltd., lot number: 20061020;

Carboxymethyl starch sodium (CMS-Na), pharmaceutical grade, Dutch DMV company;

Cross-linking sodium carboxymethyl cellulose (CCNa), pharmaceutical grade, German JRS company;

Polyvinylpolypyrrolidone (PVPP XL) and polyvidone (PVP K-29/32), pharmaceutical grade, ISP company;

Microcrystalline Cellulose (MCC); Magnesium stearate, pharmaceutical grade, A Hua Pharmacy stock Co., Ltd is chatted in Shandong;

Micropowder silica gel (SiO ₂), the meticulous silica gel chemical industry company limited of the upright letter in sea, Qingdao;

Lactose, happy (Meggle) company of German U.S. agent.

2 methods and result

2.1 disintegration time mensuration method

Because of the disintegrate of oral cavity quick disintegrating slice is very rapid, be difficult to measure according to disintegration time mensuration method conventional in the pharmacopeia, still there is not unified method at present.According to the characteristic of fast disintegrating tablet,, the assay method of disintegration time in the Pharmacopoeia of the People's Republic of China has been done suitable modification with reference to 29 editions American Pharmacopeias.Promptly adopt the device of measuring disintegration in two appendix of Pharmacopoeia of the People's Republic of China version in 2005, just do not start disintegration tester, use resting state; Get in a slice speed disintegrating tablet and the hanging basket, water is medium at every turn, and temperature is 37 ℃, and the disintegrating tablet contact water surface begins to clock with stopwatch rapidly, passes through screen cloth fully until granule.

2.2 the selection of disintegrating agent

2.2.1 the kind of disintegrating agent is to EFFECT OF CORK STOPPER

With L-HPC, PVPP XL, CMS-Na, CCNa are disintegrating agent, to measuring disintegration, the results are shown in Table 1.

The kind of table 1 disintegrating agent is to EFFECT OF CORK STOPPER

As can be seen from Table 1, the disintegrate effect of CCNa (cross-linking sodium carboxymethyl cellulose) is best, PVPP XL (polyvinylpolypyrrolidone) is suitable with CMS-Na (carboxymethyl starch sodium) disintegrate effect, but because PVPP XL, existing disintegrate effect also has certain adhesive effect, therefore select for use CCNa and PVPP XL to unite and cook disintegrating agent, and can remove PVP K-29/32.

2.2.2 orthogonal test

Prescription is by indene 2.5%, adjuvant CCNa, PVPP XL, MCC, SiO ₂, compositions such as magnesium stearate wherein influence the prescription factor CCNa of oral cavity disintegration tablet, PVPP XL, micropowder silica gel adopts orthogonal design to be designed to the orthogonal test of four factors, three levels by L9 (34) orthogonal table, investigates each factor EFFECT OF CORK STOPPER and screening are write out a prescription.The orthogonal test scheme sees Table 2, the results are shown in Table 3.

Table 2 factor level table L9 (34)

Table 3 orthogonal experiments table

Consumption＞magnesium stearate consumption＞SiO2 consumption of the consumption＞PVPP XL that is CCNa is closed in table 3 prompting, each factor to the primary and secondary that influences disintegration.Under the orthogonal test condition optimum level be combined as A2B3C3D2, promptly the CCNa consumption is 8%, PVPP XL consumption is 10%, SiO ₂Consumption is 1%, and the magnesium stearate consumption is 0.1%.Find that in 2.2.1 test some granule is excessive, therefore when selecting optimum level to test, adopted make principal agent and adjuvant cross 100 mesh sieves respectively after, mix the method for direct compression and carry out, between 30s～42s, can meet the demands disintegration as a result.

For example, the optimization formula of the quick-release medicinal composition that obtains by screening technique of the present invention consists of (percentage by weight):

Active constituents of medicine 2.5%

CCNa 8％

PVPP 10％

SiO ₂ 1％

Magnesium stearate 0.1%

MCC 25％

Lactose 50%

Vanillin 0.3%

Citric acid 2.5%

Aspartame 0.6%

The present invention also provides the preparation method of quick-release medicinal composition of the present invention, and step is as follows: after indene and adjuvant are crossed 100 mesh sieves respectively, according to above-mentioned optimized proportion and drug content with principal agent, CCNa, PVPPXL, MCC, SiO ₂, lactose, vanillin, citric acid, aspartame progressively increase by equivalent in right amount and add the magnesium stearate mixing again behind the method mixing, adopts direct powder compression to prepare sheet and heavily be 200mg, hardness is the tablet of 30N～80N, promptly gets quick-release medicinal composition.

(2) quality control

The present invention also provides the method for quality control of quick-release medicinal composition of the present invention, and step is as follows:

Adopt high performance liquid chromatography (HPLC), the UVD detector; Chromatographic column is the C8 post; Mobile phase is acetonitrile-phosphate buffer (pH is 6.8) (38/62); Ultraviolet detection wavelength 228nm; Flow velocity 1.0ml/min, sample size 20 μ l, column temperature is a room temperature.The record chromatographic peak area is by the content of external standard method with indene in the calculated by peak area test sample.

Quick-release medicinal composition provided by the invention need not drinking-water when taking, can rapid disintegrate become subparticle in the oral cavity, and its disintegration rate is fast, and is rapid-action, absorbs soon no first pass effect, bioavailability height; Dose is little simultaneously, and dosage is accurate, and the content content difference is little, steady quality.Be particularly suitable for going into a coma or the wounded of dysphagia, infant, old people take.Simultaneously the correctives that provides of the applicant has and does not contain sugar, high sugariness is arranged, low heat energy, good taste, avirulence and the characteristics such as side effect of not having sucrose, effectively cover the bad sense of taste of medicine, improved patient especially child, diabetics, old man and particular patients ' compliance greatly.

Before the present invention of disclosure and description sedative hypnotic drug indene and rapid-release vehicle compositions thereof, should understand and the invention is not restricted to concrete structure disclosed herein, method step and material, because can change these structures, method step and material.Should also be appreciated that term used herein just in order to describe specific embodiments, is not in order to limit, because scope of the present invention is just by accompanying Claim and its equivalents.

Further specify the present invention by the following examples, but not as restriction of the present invention.

[embodiment 1]

Indene 10mg

Cross-linking sodium carboxymethyl cellulose 25mg

Polyvinylpolypyrrolidone 40mg

Silicon dioxide 3mg

Magnesium stearate 1mg

Microcrystalline Cellulose 20mg

Lactose 90mg

Vanillin 1mg

Citric acid 8mg

Aspartame 1mg

After principal agent and adjuvant crossed 100 mesh sieves respectively, according to above-mentioned optimized proportion and drug content principal agent, CCNa, PVPP XL, MCC, SiO2, lactose, vanillin, citric acid, aspartame are progressively increased by equivalent and to add the magnesium stearate mixing again behind the method mixing, adopt direct powder compression to prepare sheet and heavily be 200mg, hardness is the tablet of 30N～80N, promptly.

[embodiment 2]

Indene 5mg

Cross-linking sodium carboxymethyl cellulose 30mg

Polyvinylpolypyrrolidone 30mg

Silicon dioxide 3mg

Magnesium stearate 1mg

Pregelatinized Starch 50mg

Lactose 71mg

Vanillin 2mg

Citric acid 6mg

Aspartame 2mg

Preparation method is with embodiment 1.

[embodiment 3]

Indene 10mg

Cross-linking sodium carboxymethyl cellulose 50mg

Polyvinylpolypyrrolidone 40mg

Silicon dioxide 3mg

Magnesium stearate 1mg

Lactose 59mg

Pregelatinized Starch 25mg

Vanillin 1mg

Citric acid 8mg

Aspartame 1mg

Preparation method is with embodiment 1.

[embodiment 4]

Indene 10mg

Cross-linking sodium carboxymethyl cellulose 35mg

Polyvinylpolypyrrolidone 35mg

Silicon dioxide 5mg

Magnesium stearate 1mg

Starch 31mg

Lactose 80mg

Honey peach essence 1mg

Citric acid 10mg

Maltose alcohol 2mg

Preparation method is with embodiment 1.

Should be realized that,, can under the situation that does not break away from principle of the present invention and scope, carry out various improvement although narrated specific embodiment of the present invention at this for illustrative purposes.Therefore.The present invention is unrestricted except appended claim.

Claims (4)

1. a quick-release medicinal composition is characterized in that comprising indene and pharmaceutically acceptable carrier, and indene has the structure of formula (I):

Formula (I),

The percentage by weight of its each component is:

Indene 2-5%

Cross-linking sodium carboxymethyl cellulose 8%

Polyvinylpolypyrrolidone 10%

Micropowder silica gel 1%

Magnesium stearate 0.1%

Surplus is filler and correctives.

2. quick-release medicinal composition according to claim 1 is characterized in that described filler is selected from one or more in microcrystalline Cellulose, pregelatinized Starch, mannitol, lactose, dextrin, the starch.

3. quick-release medicinal composition according to claim 1 is characterized in that described correctives is selected from one or more in citric acid, honey peach essence, maltose alcohol, saccharin sodium, protein sugar, sucrose, vanillin, Mentholum, aspartame, the stevioside.

4. the application of the described quick-release medicinal composition of claim 1 in preparation treatment sleep disorder medicine.