CN100413504C - Medicinal resin biological adhering slow-releasing liquid prepn. contg. aciclovir, and its prepn. method - Google Patents

Abstract

The present invention discloses an acyclovir drug resin bioadhesive slow release liquid preparation which is an antiviral drug and is admitted once during one day, and a preparation method of the acyclovir drug resin bioadhesive slow release liquid preparation. The preparation contains acyclovir and polymers which can be accepted on the aspect of pharmacology. According to the weight percentage, the preparation contains 30 to 90% of acyclovir, 10 to 70% of auxiliary materials, and auxiliary materials as the rest. The auxiliary materials having a slow-release function are ation exchange resin and ethyl cellulose and/or acrylic resin. The auxiliary material having an adhesive function is hydroxypropyl methylcellulose. Compared with a quick release preparation, the slow release preparation of the present invention can keep effective blood drug level within 24 hours and enhance the curative effects, and has the advantages of less toxic side effect, convenient administration and carrying, and reduced administration time. The preparation needs to be admitted once during one day. The acyclovir drug resin bioadhesive slow release liquid preparation of the present invention can be used as an antiviral drug.

Description

Acyclovir medical resin bioadhesive slow release liquid preparation and preparation method thereof

Technical field:

The present invention relates to medical technical field, exactly it is antiviral agents acyclovir medical resin bioadhesive slow release liquid preparation that was administered once in a kind of a day and preparation method thereof.

Background technology:

Acyclovir has another name called acycloguanosine (Aciclovir is called for short ACV), is the ucleosides antiviral agents.Chemistry 9-[2-hydroxyl ethoxymethyl by name] guanine.ACV is at first developed by U.S.'s Proview (B.W) company abroad, and in JIUYUE, 1981 is at first gone on the market, and domestic have the Hubei institute of Pharmaceutical Industry to take the lead in synthesizing in 1979, enters medical market in 90 years.Now by lyophilized acyclovir powder pin, tablet, capsule, eye drop, syrup, and external-application cream, multiple dosage form listing such as suppository.

Acyclovir is as antiviral agents, and antiviral spectrum is wider.To herpes simplex I, the active maximum of II type virus is taken second place to varicella zoster virus.Clinical report has inhibitory action to hepatitis B virus in recent years, to skin, and genital infection, HIV sufferers and other immunocompromised patients also have than the obvious treatment effect.Its antiviral mechanism is: be converted into monophosphate under the thymidylate kinase catalysis of ACV encoding viral in virus infected cell, further form triphosphate (ACV-TP) then.ACV-TP is the activated form of ACV, can suppress the activity of viral dna polymerase, and also alternative DGTP mixes the synthetic of DNA and the prolongation of termination DNA chain.ACV has high affinity with virus infected cell, and the concentration of ACV-TP can be greater than the 10-100 of infected cell not doubly in virocyte, so it can effectively suppress host cell DNA and duplicate, and is very little to normal cytotoxicity.The physicochemical property of ACV is: be white crystalline powder; Odorless, tasteless; Slightly soluble in glacial acetic acid and hot water, soluble,very slightly in water, almost insoluble in EC; Dissolve in rare sodium hydroxide, this product fusing point is 257 ℃.

But the difference of the absorbance follower kind of acyclovir and different.Oral absorption such as Canis familiaris L. and mice is better, but the human oral post-absorption is relatively poor, and there is an obvious individual variation, be 15-30% only, bioavailability is lower, and along with the increase bioavailability of dosage reduces on the contrary, according to the literature, ACV only absorbs in the gastrointestinal tract middle and upper part, and absorption window is narrow, effectively transports time less at gastrointestinal tract.

General preparation often needs administration several times on the one, as conventional tablet administration on the one 3 times, each 1 (30mg/ sheet).Because of pain, reason patient such as dislike trouble can consciously or unconsciously change the scheme of taking medicine, miss once or twice, levels of drugs composition fluctuations in blood plasma and the tissue is big, even continuation medication, do not reach treatment concentration in a short time yet, can only could rebuild treatment level by repeated drug taking, not only waste medicine but also incured loss through delay treatment.Oral sustained-release preparation means prolong drug effect in vivo, reduces a class new medicinal preparation of medicining times, has the minimizing toxic and side effects, improves patient's toleration and the advantages such as blood drug level that lasting stability is provided.

Although sustained-release preparation is comparative maturity, the dosage form and the preparation of particular patients ' such as suitable child and old man are very limited.Because this class patient and the difference of adult on physiological function, except the difference of dosage, the requirement of dosage form and the compliance of taking medicine also there is different requirements, solid preparation Chang Yinwei mouthfeel discomfort or dysphagias such as oral controlled-release tablet or capsule and be difficult for problems such as divided dose, and cause this type of patient's the inconvenience of taking, influence the performance with drug effect finished of normal therapeutic scheme, some film control formula sheets or slow releasing tablet are taken after broken splitting, even serious side effects takes place.And liquid preparation have absorb fast, but administered in divided doses, easily by characteristics that old man and child accepted.

The Chinese patent of at present relevant acyclovir has:

Publication number is that 1179717 Chinese patent application discloses a kind of " new pharmaceutical composition "; Publication number is that 1202359 Chinese patent application discloses a kind of " medicine for preventing sexual disease "; Publication number is that 1202357 Chinese patent application discloses a kind of " medicine for curing sexual disease "; Publication number is that 1298705 Chinese patent application discloses a kind of " Chinese medicine medicine of treatment hepatitis B and preparation method thereof "; Publication number is that 1334737 Chinese patent application discloses a kind of " the acyclovir compositions that contains dimethicone "; That publication number is that 1431203 Chinese patent application discloses is a kind of " 7-replacement-1-mix hydrogenated naphthalene-2-ketone and derivant, its synthetic method and application ";

Publication number is that 1443764 Chinese patent application discloses a kind of " containing new fused tricyclic nucleoside compound of acyclovir fragment and preparation method thereof ";

The foreign patent of relevant acyclovir has:

IPC：A61K；IPC：A61K31/70；A61K9/20；IPC：A61K31/52；A61K9/107(+3)；IPC：A61K38/06；A61K31/52IPC：A61K31/52；A61K9/08；(+1)IPC：A61K31/52；A61K9/06；(+2)IPC：C07D473/18；C07H19/06；IPC：A61KIPC：A61K31/52；A61K47/00IPC：A61K9/20；A61K31/395；IPC：A61K31/52；A61K47/36；IPC：A61K31/52；A61K47/10IPC：A61K9/06IPC：A61K31/54；C07D513/04；

More than both at home and abroad patent and document are not seen the report of relevant acyclovir medical resin bioadhesive slow release liquid preparation as yet.

Summary of the invention:

The purpose of this invention is to provide acyclovir medical resin bioadhesive slow release liquid preparation that was administered once in a kind of a day and preparation method thereof, the patient only needs take once day and can reach therapeutic effect every day.The present invention is directed to the deficiency of existing preparation, improve bioavailability of medicament by the bioadhesion means, is 600mg/ time through a large amount of biopharmaceuticies and the acyclovir consumption of determining of pharmacokinetics, to guarantee the effectiveness of novel formulation again.Carry out a large amount of preparation researches according to the character of acyclovir again, finished the development work of the bioadhesive slow release liquid suspension that was administered twice in 1st.The present invention mainly comprises principal agent, blocker, adhesive agent, impregnating agent, plasticizer, and other adjuvant such as suspensoid is formed.

The selected slow-release material of the present invention is a cation exchange resin, one or more in ethyl cellulose, the acrylic resin etc.

Adhesive agent is a hydroxypropyl methylcellulose.

Impregnating agent has methylcellulose, glycerol, one or more among the PEG4000 etc.

Plasticizer has diethyl phthalate, dibutyl sebacate, one or more among the PEG400 etc.

Suspensoid has PVP, tragcanth, Carbopol, one or more among the Avicel RC591 etc.

In vitro tests is the important means that the screening prescription is determined technology, and the quality control of preparation is had important function, mainly investigates by dissolution rate.It is release medium that the present invention adopts the 900ml 0.1mol/1HCl that handles through the degassing: rotating speed 50r/min, 37 ℃ of temperature.According to the operation of 2000 editions appendix XC of Chinese Pharmacopoeia oar method, respectively at 2,4,6,8,10, the 12h 5ml that takes a sample filters through the 0.45um microporous filter membrane, discards filtrate just, it is standby to get subsequent filtrate, in time add synthermally,, subsequent filtrate is measured absorbance in the 252nm place with the respective media of volume, calculate different time sample liquid concentration according to standard curve, investigate 24 hours accumulative total burst size and time relation.The release in vitro of acyclovir provided by the invention can make drug slow discharge in the body, and it is steady to reach blood drug level, the purpose that duration of efficacy is long.

To carry out high temperature (60 ℃), high humidity (92.5%), illumination (3000lx) according to the Aciclovir sustained-release tablet that the present invention makes, expose the air experiment, the result shows this product under high temperature, high humidity, illumination, exposure conditions of air, and stability better.

Preparation technology:

1, the preparation of medical resin

Cation exchange resin is added in an amount of simulated gastric fluid, under agitation add the medicine mixing, timing sampling, measure the concentration of solution Chinese medicine, when drug level balance to be reached during time to time change no longer, with the not bound drug of deionized water flush away resin surface, be drying to obtain the medicine carrying resin at 40 ℃-60 ℃;

2, the dipping of medical resin

It is an amount of to get the medicine carrying resin, in the aqueous solution of the PEG4000 of adding 20%, stirs the medical resin that drying and screening must be flooded 0.5 hour;

3, the preparation of medical resin bioadhesion microcapsule

At first acrylic resin and/or ethyl cellulose and hydroxypropyl methylcellulose are dissolved in the acetone or alcohol, add impregnated medicine carrying resin and plasticizer then, use the magnetic stirrer certain hour, make both homodisperse of back, form suspension, under stirring condition, this suspension added in the liquid paraffin and sorbester p17 mixed liquor of mix homogeneously, stirred in water bath to acetone or alcohol in uniform temperature volatilizes subsequently, microcapsule sucking filtration with gained, with petroleum ether, under 40 ℃ of temperature, be drying to obtain the medical resin microcapsule;

4, the preparation of medical resin microcapsule suspensoid

Thing-resin the microcapsule of getting it filled is a certain amount of, and suspending agent (PVP, tragcanth, Carbopol, one or more among the Avicel RC591 etc.) is an amount of, increases the weight of to steam water dissolution and dilution, and mix homogeneously promptly gets medicine-resin slow-release suspension.

Advantage of the present invention is: but the present invention's significant prolongation acyclovir improves local drug concentration in the holdup time of upper gi tract, thus can promote the absorption of medicine, improve bioavailability.It is that a kind of mouthfeel is good and can prolong the liquid slow-release preparation of drug effect, has a good application prospect, and feasible process, be easy to produce.

Description of drawings:

Fig. 1 is the releasing curve diagram according to the acyclovir bioadhesive slow release liquid mixed suspension preparation of embodiment 1 preparation

Fig. 2 is the releasing curve diagram according to the acyclovir bioadhesive slow release liquid mixed suspension preparation of embodiment 2 preparations

The specific embodiment:

Embodiment 1:

Acyclovir: 600mg;

Amberlite?IRP69： 500mg；

Hydroxypropyl methylcellulose K15M 50mg

PEG4000： 200mg；

PEG400： 5mg；

Diethyl phthalate: 5mg;

EC(20cps) 40mg；

PVP(K90) 8mg

Carbopol(934P) 16mg

Embodiment 2:

Acyclovir: 600mg;

Amberlite?IRP69： 500mg；

Hydroxypropyl methylcellulose K4M 60mg

PEG4000： 250mg；

PEG400： 7mg；

Diethyl phthalate: 6mg;

Eudragit?RS?100 40mg；

Eudragit?RL?100 30mg；

PVP(K30) 20mg

Avicel(RC591) 20mg

Embodiment 3:

Acyclovir: 600mg;

Amberlite?IRP69： 750mg；

Hydroxypropyl methylcellulose K100M 40mg

PEG4000： 300mg；

PEG400： 10mg；

Dibutyl sebacate: 7mg;

EC(45cps) 40mg；

Tragcanth 7.5mg

Carbopol(934P) 10mg

Embodiment 4:

Acyclovir: 600mg;

Amberlite?IRP69： 750mg；

Hydroxypropyl methylcellulose K15M 70mg

Glycerol: 200mg;

PEG400： 10mg；

Dibutyl sebacate: 5mg;

Eudragit?RS?100 30mg；

Eudragit?RL?100 25mg；

PVP(K30) 5mg

Tragcanth 15mg

Avicel(RC591) 15mg

Claims (5)

1. acyclovir medical resin bioadhesive slow release liquid preparation, it is characterized in that: said preparation contains following composition by weight percentage:

Acyclovir 30-90%

Cation exchange resin and ethyl cellulose and/or acrylic resin 10-70%

Other adjuvant surplus.

2. acyclovir medical resin bioadhesive slow release liquid preparation according to claim 1, it is characterized in that: adjuvant is a blocker, adhesive agent, impregnating agent, plasticizer, suspending agent.

3. acyclovir medical resin bioadhesive slow release liquid preparation according to claim 2, it is characterized in that: adhesive agent is a hydroxypropyl methylcellulose.

4. according to claim 1 or 2 or 3 or 4 described acyclovir medical resin bioadhesive slow release liquid preparations, it is characterized in that: when oral giving, compare with the quick releasing formulation of acyclovir, in blood plasma, produce remarkable lower average coefficient of variation on the statistics, keep bioavailability basic identical with the quick releasing formulation of acyclovir or that improve simultaneously.

5. the preparation method of an acyclovir medical resin bioadhesive slow release liquid preparation as claimed in claim 1 is characterized in that:

The preparation of a, medical resin

Cation exchange resin is added in an amount of simulated gastric fluid, under agitation add the medicine mixing, timing sampling, measure the concentration of solution Chinese medicine, when drug level balance to be reached during time to time change no longer, with the not bound drug of deionized water flush away resin surface, be drying to obtain the medicine carrying resin at 40 ℃-60 ℃;

The dipping of b, medical resin

It is an amount of to get the medicine carrying resin, in the aqueous solution of the PEG4000 of adding 20%, stirs the medical resin that drying and screening must be flooded 0.5 hour;

The preparation of c, medical resin bioadhesion microcapsule

At first acrylic resin and/or ethyl cellulose and hydroxypropyl methylcellulose are dissolved in the acetone or alcohol, add impregnated medicine carrying resin and plasticizer then, use the magnetic stirrer certain hour, make both homodisperse of back, form suspension, under stirring condition, this suspension added in the liquid paraffin and sorbester p17 mixed liquor of mix homogeneously, stirred in water bath to acetone or alcohol in uniform temperature volatilizes subsequently, microcapsule sucking filtration with gained, with petroleum ether, under 40 ℃ of temperature, be drying to obtain the medical resin microcapsule;

The preparation of d, medical resin microcapsule suspensoid

Thing-resin the microcapsule of getting it filled is a certain amount of, and suspending agent is an amount of, increases the weight of to steam water dissolution and dilution, and mix homogeneously promptly gets medicine-resin slow-release suspension.

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