CN1953734A - Pharmaceutical composition for improving palatability of drugs and process for preparation thereof - Google Patents

Pharmaceutical composition for improving palatability of drugs and process for preparation thereof Download PDF

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CN1953734A
CN1953734A CNA2004800430930A CN200480043093A CN1953734A CN 1953734 A CN1953734 A CN 1953734A CN A2004800430930 A CNA2004800430930 A CN A2004800430930A CN 200480043093 A CN200480043093 A CN 200480043093A CN 1953734 A CN1953734 A CN 1953734A
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medicine
lipid
compositions
polymer
acid
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CN100548270C (en
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阿尼奥帕·拉梅什·曼乔治
莫汉·戈帕克里希纳·库尔卡尼
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Council of Scientific and Industrial Research CSIR
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention discloses compositions, comprising a lipid-polymer matrix to mask the bitter or unpleasant taste of the medicament. The lipid or a blend of lipids, are used in combination with the pH dependent polymer where the said polymer is acid soluble or swellable. The process for the preparation of taste masked pharmaceutical compositions of the bitter drugs comprising the said lipid-polymer compositions are disclosed. The concomitant use of the acid soluble polymer, which remains collapsed at the pH of saliva, inhibits the release of drug at that pH and hence they further help in bitterness inhibition. The said compositions deliver substantial amount of the bitter drug immediately at the gastric pH with improved palatability.

Description

Improve Pharmaceutical composition of palatability of drugs and preparation method thereof
Invention field
The invention provides the Pharmaceutical composition that improves palatability of drugs.More specifically, the present invention relates to by medicine being dispersed in the bitterness that suppresses medicine in lipid-polymeric matrix.Compositions of the present invention discharges a large amount of medicines immediately in the pH of stomach.The present invention also relates to these preparation of compositions methods.
Background of invention
Though developing many induction systems to be used for different route of administration, for example oral administration, parenteral, nose administration and transdermal administration or the like, but for drug conveying, oral route is still the most attractive, because this mode of administration is simple, convenient, Noninvasive and common medicament delivery method.Conventional peroral dosage form comprises: such as the liquid mixture of solution, suspensoid, such as the solid dosage forms of tablet and capsule and liquid-filling capsule or the like.This solid dosage forms also improves according to needed therapeutical effect, as controlled release, slow release or extended release.Yet, the patient at extreme age, for example child and old people often feel difficulty when swallowing solid oral dosage form.For these patients, drug main will provide with liquid dosage form, as solution, emulsion and suspension.But these dosage forms are exposed to taste bud with active pharmaceutical ingredient perception ground usually, and when medicine had ill-sorted taste or bitterness, this just became very serious problem.
The bitterness of the medicine of oral administration is unfavorable factor in many aspects.Taste is the important parameter of control compliance.The disagreeable taste of medicine causes dysphagia or causes that the patient escapes takes medicine, thereby causes patient's low compliance.Normally unsuccessful in the taste of covering utmost point bitter medicine thing such as the conventional taste masking technology of using sweeting agent, aminoacid, flavoring agent, these utmost point bitter medicine things for example are quinine, berberine (barberin), etoricoxib, antibiotic is as levofloxacin, ofloxacin, Sparfloxacin, ciprofloxacin, cefuroxime axetil (cefuroxime axetil), erythromycin and clarithromycin.Therefore the taste masking technology is considered to important, and develops this technology by many researcheres.
When medicine has ill-sorted taste and bitterness, taste masking is a subject matter, and this problem is not only limited to liquid oral compositions, as solution, dry syrup and suspension, in the process for preparation of chewable tablet or dispersible tablet, also may run into, but wherein these dosage forms make active component perception ground be exposed to taste bud usually.Depend on the type of dosage form, having made ins all sorts of ways overcomes the disagreeable taste and the bitterness of medicine.Initial stage has attempted being used for the several different methods of taste masking, and described method comprises to be made spent ion exchange resin, bitterness medicine and medicine can accept excipient compound and by lipid and multiple polymeric material medicine is wrapped quilt.Adopt lipid to prepare some utmost point bitter medicine things.
The 4th, 797, No. 288 U.S. Patent Publications new delivery system, this delivery system based on the hydrophobic base bag by core, make coating postpone the hydration of this core.This induction system comprises and is designed for the dried drug particles of chewing or swallowing.The hydrophobic base coating that postpones the hydration of core comprises about 200-400% weight ratio of medicine.This hydrophobic material has 25-100 ℃ fusing point.This induction system comprises the fatty acid of 61-95% weight ratio.
No. 1323161 British patent discloses uses fusing point to be no more than 95 ℃ lipid bag by the acetoxy-methyl benzylpenicillin.Finish the bag quilt of lipid by the spraying freezing method.The powder of the quilt that wraps is to recombinate in 6.5 o'clock at pH.Said composition protection penicillin avoids making moist, and also covers bitterness.But because the hydrophobic property of lipid, the independent application of lipid is tending towards postponing the release of this medicine.
No. 2081092 British patent discloses the application of wax material and high-molecular weight water-swellable material.Add this water-swellable material to improve dissolubility, this helps to increase the absorption of medicine.But the common application of water-swellable material and lipid has limited application in compositions, because these compositionss often are being used for recombinating the aqueous medium of dry syrup or also leaching medicine in suspension.
The 5th, 405, No. 617 U.S. Patent Publications be used to prepare the solventless method of the compositions of taste-cover, the spraying that this solventless method relates to the stearoyl stearate of fusing is solidified and mixed active medicine subsequently.
The 4th, 865, No. 851 U.S. Patent Publications cover the method for utmost point bitter taste of the acetoxyl group ethyl ester of cefuroxime with particulate form, this method is wrapped by to cover this taste by the complete coating with the mixture of lipid or lipid.The granule of bag quilt is introduced in the aqueous suspension.But used lipid is insoluble can being dispersed or dissolved in the gastro-intestinal Fluid in water.The lipid that is used for taste masking in said composition is 95-10%, and cefuroxime axetil is 5-90%.Preferred range is that lipid is 90-70%, and cefuroxime axetil is 10-30%.Disclosed embodiment shows that medicine is more than or equal to 1: 4 to the ratio of lipid in this patent.
People such as Robson (H.J.Robson, D.Q.M.Craig, D.Deutsch, InternationalJournal of Pharmaceutics, 190,1999,183-192) the cefuroxime axetil microgranule of having studied stearic acid bag quilt in distilled water and pH be 5.9,7 and pH be dissolubility in 8 the Sorensen improvement buffer.This studies show that when arriving intestinal the release of this medicine from the cefuroxime axetil microgranule of stearic acid bag quilt increases.This coating helps to cover the taste of cefuroxime axetil.People such as Robson (H.J.Robson, D.Q.M.Craig, D.Deutsch, International Journal of Pharmaceutics, 195,2000,137-145) influence of buffer compositions to the release of cephalo furan XINYI acyl-oxygen ethyl ester from the cefuroxime axetil microgranule of stearic acid bag quilt also disclosed.The buffer that is studied comprises phosphate buffer, citric acid phosphoric acid salt buffer, blended borate buffer and the phosphate buffer of Sorensen improvement, and according to pharmacopeia 1994, the pH scope of all these buffer is 7.This studies show that the effect to releasing mechanism of pH and Na ion concentration.Stearic acid is effective with this releasing mechanism of interaction partners that contains the buffer medium of sodium ion.
Above-mentioned open in, the release of research cefuroxime axetil in alkaline medium.People such as Dantzig are (referring to Anne H.Danzig, Dale C.Duckworth, Linda B.Tabas, Biochimica et Biophysica Acta 1191,1994,7-13) show that cefuroxime axetil is become cefuroxime by esterase hydrolyzed in enteric cavity, reduce the concentration of cefuroxime axetil in enteric cavity, cause absorbing and reduce and the low bioavailability of cefuroxime axetil in human body.Therefore the preparation such as the medicine of cefuroxime axetil should be such, and promptly said preparation discharges this medicine in upper stomach zone rather than the pH at intestinal.Cefuroxime axetil has had only the bioavailability of 32-50%, and any reason owing to the preparation aspect all should minimize declined bioavailability of oral administration.
The 4th, 897, No. 270 U.S. Patent Publications the cefuroxime axetil tablet of thin film bag quilt to cover the taste of this bitterness medicine, make this film coating in the several seconds implosion, tablet is disintegrate at once.This preparation is used to improve the bioavailability of cefuroxime axetil.This patent is instructed us in case contact with aqueous medium, and cefuroxime axetil forms gelatinous material.This gelation is temperature dependent, and under～37 ℃ temperature, and promptly the physiological temp in the tablet generation disintegrate of oral administration issues living gelling.In addition, this patent is also instructed us and is passed film coating because moisture slowly permeates, so when oral administration, have the gelation conventional film-coated, that tablet comprise cefuroxime axetil in core causes medicine.The formation of gel causes the bad disintegrate of tablet core, thereby causes bad stripping, absorption and the bioavailability of cefuroxime axetil.Therefore, should so be prepared,, and do not have described buffer slowly to penetrate into the situation of coating material even said composition discharges this medicine at once in the territory, gastric area such as the medicine of cefuroxime axetil.The coating material that this patent also instructs us to be used for cefuroxime axetil should be such, and promptly it discharges described medicine immediately before gelation takes place.
The 5th, 972, No. 373 U.S. Patent Publications the taste masking Pharmaceutical composition of good bioavailability is provided.Said composition have the high polymer formed by polyvinyl acetal diethyl amino yl acetate, solubilized under one's belt aminoalkyl methacrylate copolymer Eudragit E and be used for the monoglyceride of taste masking: glyceryl monostearate.This coated composition is applicable to the medicine such as cefuroxime axetil, and it is absorbed from the upper stomach zone better.But cefuroxime axetil has shown and the negative interaction such as the polymer of Eudragit E based on the aminoalkyl methacrylate.
People such as Alonso (M.J.Alonso, M.L.Lorenzo-Lamosa, M.Cuna, J.L.Vila-Jato and D.Torres, Journal of Microencapsulation, 1997, Volume 14, No.5 607-616) has studied utmost point bitter medicine thing cefuroxime axetil has been encapsulated in the acrylic acid microsphere of pH sensitivity to be mixed with the suspension dosage form.This studies show that cationic polymer Eudragit E (polymer that comprises dimethyl amino ethyl methacrylate) shows the negative interaction with cefuroxime axetil.
The 4th, 132, No. 753 U.S. Patent Publications be used for from comprising the method for compositions controllable release medicine wax sample material and that have 30 ℃ of-100 ℃ of fusing points.Stir the lipid drug mixture continuously under the temperature of this wax sample material fusing, this drug powder sinks in the melted surface of this wax sample material.By the material of cooling fusing, gradation subsequently obtains the granule of bag quilt.Disclosed wax sample material comprises glyceryl monostearate, hydrogenated fat and wax shape aliphatic alcohol.The 6th, 589, No. 955 U.S. Patent Publications the pediatric formulation of taste masking of Gatifloxacin.Is 1: 1.8 to 1: 2.3 with Gatifloxacin to the ratio of fatty acid, uses the co-precipitation that forms the taste masking of Gatifloxacin such as the fatty acid of stearic acid or Palmic acid, and preferred ratio is 1: 2.1.United States Patent (USP) the 6th, 156 discloses taste masking, the solid oral rapidly disintegrating dosage form method of preparation for No. 339, and described dosage form comprises the dispersible carrier of water, filler, pharmaceutically active substance and lipid, makes this pharmaceutically active substance and this contaminated with lipid.The part by weight of pharmaceutical actives confrontation lipid is 1: 1 to 1: 10.
No. 2002138034 Japanese Patent Application Publication comprise the antihistamine drug chlorphenamine maleate of Bodhisattva flavor and the fatty acid of taste masking is stearic chewable tablet.Said composition is included in 0.5pts.wt. extremely less than the fatty acid in the every 1pt.wt. medicine of the 3pts.wt. fatty acid scope.
The chewable tablet of using lipid material drug coated is disclosed No. 2784895 French Patent (FRP).Use is 37-75 ℃ of lipid that melts down.This patent disclosure to be used to wrap by the lipid of described medicine be 10%, be preferably 2-5%.
Such as can bite into pieces/the lipid material that is used for the taste masking purposes in masticable tablet or the particulate preparation causes the rapid release of medicine when this lipid coating of the process of chewing breaks, yet this causes feeling bitterness.
The 6th, 485, No. 742 U.S. Patent Publications comprise the bag quilt of the hydrophilic core material of vitamin, the lipid by will fusing dropwise is added on the core substance of liquefaction, makes the lipid of this fusing solidify and form coating on this core substance and realizes described bag quilt.The bag that is undertaken by the lipid material has been covered the bad smell of vitamin.Used coating material is the 0.1-30%w/w of total coating material.PCT International Application No. WO 00/61119 discloses the microencapsulation method of medicine, mixes with coating materials fusing and that keep lasting stirring by this medicine and realizes this microencapsulation method.Under agitation, with the material cooled of this fusing to produce microcapsule.
The 4th, 837, No. 381 U.S. Patent Publications comprise biological activity protein or peptide wax or fat sustained release microsphere agents.The invention discloses the described fat that in this microball preparation, used 30-95%w/w or protein or the peptide of wax and 2-70%.
The 6th, 1174, the microsphere by the thermoforming preparation of compositions is disclosed in No. 52 United States Patent (USP)s, said composition comprises the pharmaceutically active substance of 5-90%, the glyceryl monostearate of 10-90% and Polyethylene Glycol and the glyceryl palmitostearate of 2-15%.
No. 2001288117 Japanese Patent Application Publication adopt fatty glyceride and optional easy water-soluble substances to the taste masking of medicine Rebamipide (rebamipide) oral formulations.Water solublity or swelling material are used for strengthening this medicine and discharge from lipid matrix.The common application of water-soluble substances and lipid has limited their application in the lipid oral formulations.
Pharmaceutical composition with improved taste is disclosed in PCT International Application No. WO 00/06122.Being dispersed in medicine based on 1 part of this medicine is in the fatty acid ester of glycerol substrate of 1.5-15 part weight ratio.The drug particles of this fatty acid bag quilt is soluble or enteric polymer (enteric polymer) the bag quilt by water solublity, water-insoluble or stomach further.
The delivery system of substantially tasteless is disclosed in No. 0670716 European patent.This induction system comprises active component, has the wax core material of 50 ℃ of-200 ℃ of fusing points and the substrate of hydrophobic polymer.The amount that is present in the hydrophobic material of this induction system is the 3-10% weight ratio of this substrate, and is present in the 15-85% weight ratio of the amount of the wax core in this substrate for this substrate.
In PCT International Application No. WO 00/18372, disclose to provide and covered the granule that is used for oral administration bitterness medicine taste, that obtain by spray solidification well.This granule comprises medicine with unpleasant taste and has 40 ℃-120 ℃ fusing point, is used from the Lipid carriers of covering this unpleasant taste with polymer one.Polymer or enteric polymer or gastric solubleness polymer with this lipid use in conjunction.
The PCT International Application No. WO discloses the oral fast-dispersing type that comprises the microgranule that is used to strengthen bioavailability for No. 03/059349.This microgranule comprises medicine: zolpidem, as the fatty acid such as monoglyceride of spheronisation aid, such as the solubility enhancing agent of Polyethylene Glycol with cover the polymer coating of product taste.
No. 2004091536 U.S. Patent Application Publication the granule of the be reassembled as Ketek suspension done, this granule comprises Ketek nuclear and wax-like materials, this wax-like materials adjoining land with lipid and polymer coating bag by twice with randomly contain the coating bag quilt of lipid and polymer with another.
PCT International Application No. WO 01/91761 discloses the substrate that comprises bitterness medicine clarithromycin, fatty acid glyceride or stearyl alcohol and polymer, and described polymer is selected from hydroxypropylmethyl cellulose phthalate, hydroxypropyl emthylcellulose acetic acid succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S.This substrate provides the oral formulations of no clarithromycin bitterness.
Following patent and patent application disclose independent lipid or with the purposes of lipid in the Pharmaceutical composition of medicine such as other inert matter associating of polymer: WO 02/72072; US 4,880, and 634; US 5,571, and 533; US 5,169, and 645; US 6,086, and 920; WO99/32092; US 6,139, and 877; US 5,891, and 476; EP 0855183.
Lipid with such as water repellency, avirulence with not have odour nuisance relevant with the character of color, and they give compositions slick quality.These character make lipid become the good candidate that taste masking is used.But fatty acid does not show good film property, and therefore, because medicine must be dispersed in this lipid matrix fully, the complete coating with independent lipid needs more substantial lipid.Because medicine must be dispersed in the lipid matrix, also need the lipid of a large amount of fusings such as melt granulation and the spraying technology of solidifying.
Lipid is hydrophobic in nature, so when using lipid with higher amount, the release of grievous injury medicine.Above-mentioned disclosed many preparations use the combination of polymer and lipid, to quicken the release of medicine.The common application of water-swellable or water-soluble polymer and lipid provides the release immediately of desirable medicine, but desirable taste masking effect can not be provided, especially for liquid oral compositions or the particulate situation that is used to recombinate.PH dependent/non-dependent polymer and the use in conjunction of lipid in taste masking such as ethyl cellulose provide such compositions, and said composition prevents medicine leaching in as the aqueous medium of oral liquid environment, postpone the release of this medicine when still absorbing.Similarly, adopt the compositions of enteric polymer and lipid associating to be tending towards postponing drug release, arrive intestinal up to them.Above-mentioned discloseder patent application use in conjunction enteric polymer Eudragit E and lipids, it provides the release immediately and the taste masking effect of medicine.But Eudragit E showed swelling at pH up to 5.5 o'clock, and demonstrated and such as the interaction of the some drugs of cefuroxime axetil.
Therefore need the such preparation of exploitation, the needed total amount of polymers that is used for the taste masking purposes reduces, yet described compositions is carried a large amount of medicines in the territory, gastric area, and does not postpone.In addition, this polymer should be such, i.e. its reorganization for taste masked particle provides pH scope widely.
Now; we find; open and claimed pH sensitive polymer in our copending application PCT/IN03/00390 and PCT/IN03/00392; when with unite such as the lipid of fatty acid, fatty acid ester and aliphatic alcohol the bag that is used for medicine by the time, it shows the bitterness of covering medicine when pH of saliva.Compare for the 10/971st, No. 534 with us patent application PCT/IN03/00390, PCT/IN03/00392 and the U.S. Patent application of while pending trial, the amount of finishing the needed polymer of effective taste masking is lower.The amount that realizes the lipid that taste masking is required is also than United States Patent (USP) 4,865, significantly reducing in 851.In addition, under identical condition, the speed that medicine discharges in lipid-polymeric blends from the present invention is significantly than those speed height that can obtain from the preparation based on lipid or lipid mixtures.
Goal of the invention
The objective of the invention is to use the mixture of pH dependent polymers and lipid, no matter this lipid is the mixture of independent lipid or lipid.
Another object of the present invention provides the taste masking preparation of the mixture of the combination with polymers that comprises lipid and sour solvable or swellable, and this taste masking preparation makes it possible to carry at once a large amount of medicines, guarantees to improve palatability simultaneously.
Another object of the present invention provides pharmaceutical preparation, wherein mainly by using synthetic especially pH sensitive polymer that described medicine is dissolved in the stomach, this pH sensitive polymer dissolves or swelling under the condition of acidic pH of stomach, but does not dissolve in nearly neutrality or neutral pH.
Another object of the present invention provides lipid-polymeric matrix with drug coated, makes the amount of required polymer unite to use because of itself and lipid and reduces, and owing to suppress the amount that the synergism of this lipid-polymeric matrix of bitter taste of drug has also reduced lipid.
Another object of the present invention be with the lipid that medicine is dispersed in fusing in case spraying solidify or the amount of the required lipid of melt granulation is compared, with lipid-polymer solution drug coated so that reduce the amount of the lipid that needs.
Another object of the present invention is the development group compound, and said composition can be used to cover the bitterness of medicine in multiple dosage form, makes it possible to this medicine of rapid release when picked-up simultaneously, thereby does not change the availability of this medicine.
An also purpose of the present invention provides the compositions of covering the medicine taste that does not discharge medicine under the pH value of saliva.
A further object of the present invention is the granule of exploitation taste masking, and this granule can be used for such as in suspension, the dry syrup oral liquid and in the solid dosage forms such as chewable tablet, rapid release sheet and conventional tablet.
Summary of the invention
Therefore, the invention provides the Pharmaceutical composition that comprises medicine, lipidic component and pH dependent polymers, wherein this pH dependent polymers is acid soluble or swellable and has formula: P[A (x)B (y)C (z)], wherein P is for comprising (A) hydrophobic monomer, (B) alkaline monomer and (C) polymer of hydrophilic monomer, and (x)=30-95%, (y)=5-70%, (z)=0-60%, all percentage ratios are all represented with w/w, so that x+y+z=100%.
In one embodiment of the invention, described pH dependent polymers is selected from the polymer of acid soluble polymer or sour swellable, comprises the monomers methyl methacrylate, hydroxyethyl methylacrylate and the vinylpyridine that are respectively 50-75%, 15-35% and about 5-15%w/w.
In another embodiment of the present invention, described lipidic component is selected from ester, aliphatic alcohol, hydro carbons, neutral fat and the wax of fatty acid, fatty acid.
In another embodiment of the present invention, described fatty acid is selected from saturated or unsaturated fatty acid.
In another embodiment of the present invention, described saturated fatty acid comprises the aliphatic carboxylic acid of long-chain, as lauric acid, stearic acid and Palmic acid.
In another embodiment of the present invention, described aliphatic alcohol comprises the aliphatic alcohol of long-chain, as stearyl alcohol, palmityl alcohol and spermol.
In another embodiment of the present invention, the ester of described fatty acid comprises the ester of glycerol and fatty acid, as glyceryl monostearate, monopalmitin, tripalmitin, docosane acid glyceride and castor oil hydrogenated.
In another embodiment of the present invention, the combination of described lipidic component with single lipid or lipid is used.
In another embodiment of the present invention, the pH dependent polymers of described compositions is 1: 0.5 to 1: 40 to the ratio of lipid, is preferably 1: 1 to 1: 35.
In another embodiment of the present invention, the medicine of described compositions is 1: 0.1 to 1: 8 to the ratio of lipid, is preferably 1: 0.4 to 1: 6.
In another embodiment of the present invention, the medicine of described compositions is 1: 0.1 to 1: 1 to the ratio of pH dependent polymers, is preferably 1: 0.1 to 1: 0.6.
In another embodiment of the present invention, described medicine is used with itself or with the form of the acceptable salt of its medicine or ester or amide.
In another embodiment of the present invention, described medicine is selected from macrolide antibiotics, for example, and erythromycin, azithromycin and clarithromycin; Fluoroquinolones, for example, ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin; Cephalosporins is made up of cefuroxime, cefaclor, cephalexin, cefadroxil, Cefpodoxime Proxetil (cepfodoxime proxetil); The anti-inflammatory analgesic medicine of nonsteroidal is as ibuprofen, aspirin, acetaminophen and diclofenac sodium; The COX inhibitor 2 is as etoricoxib and celecoxib; Antihistaminic is as cimetidine, ranitidine, famotidine and chlorphenamine maleate; The oxazolidine ketone is as Linezolid and such as the other medicines of dextromethorphan.
In another embodiment of the present invention, described compositions does not discharge medicine when pH of saliva, but in the pH seen in stomach≤3, the medicine that rapid release is a large amount of.
In another embodiment of the present invention, described compositions is a particle form, and described medicine is dispersed in the polymer lipid matrix itself, and perhaps described compositions is the medicine acceptable forms.
In another embodiment of the present invention, described Pharmaceutical composition is a drink form, as dry syrup or suspension.
In another embodiment of the present invention, described Pharmaceutical composition is the form of solid dosage forms, as chewable tablet, effervescent tablet, quickly disintegrating tablet or dispersible tablet.
Liquid of the present invention provides preparation to comprise the method for the Pharmaceutical composition of medicine, lipidic component and pH dependent polymers, and wherein this pH dependent polymers is acid soluble or swellable and has formula: P[A (x)B (y)C (z)], wherein P is for comprising (A) hydrophobic monomer, (B) alkaline monomer and (C) polymer of hydrophilic monomer, and (x)=30-95%, (y)=5-70%, (z)=0-60%, all percentage ratios are all represented with w/w, so that x+y+z=100%, described method comprises by being selected from following technology and described medicine is disperseed or is coated in the substrate of polymer and lipidic component: microencapsulation, spray drying, melt granulation, tray dried method and spraying are solidified.
In an embodiment of described method, described method comprises the microencapsulation that adopts the emulsified solvent evaporation, this microencapsulation is undertaken by following steps: by described polymer and lipid are dissolved in the organic solvent that is selected from chloroform and dichloromethane to form lipid-polymer solution, described medicine is joined in this solution to form organic facies, this organic facies is dispersed in the distilled water of the polyvinyl alcohol that contains the 0.1%-1%w/w amount, under 25 ℃-30 ℃ temperature, described mixture with the speed of about 500-1000rpm mechanical agitation 2-3 hour continuously, is separated the microgranule that obtains by filtration and the described granule 5-10 of lyophilizing hour then.
In another embodiment of described method, described method comprises carries out gradation with contain the described polymer of described medicine and the dichloromethane of lipid or the chunk of chloroformic solution cast with dissolving or discrete form, and desolvates by evaporating to remove under 25 ℃ to 30 ℃.
In another embodiment of described method, under agitation reach and keep temperature to be higher than under the condition of 3 ℃-5 ℃ of lipid fusing points, described polymer and described medicine are dispersed in the lipid of fusing to obtain the material of fusing, the material that will melt little by little cools off to obtain granule then, subsequently granule is sieved.
In another embodiment of described method, described method comprises that the lipid-polymer solution spray drying that will contain described medicine is to obtain microgranule, this microgranule is dried in the dry gas existence subsequently, and described dry gas is selected from nitrogen, argon, carbon dioxide and air.
Detailed description of the invention
The invention provides oral Pharmaceutical composition, this Pharmaceutical composition suppresses bitterness, unpleasant taste and other disagreeable taste of active component effectively.More specifically, the present invention relates to the application of lipid-polymeric blends, in the pH of stomach, discharge a large amount of medicines when this lipid-polymeric blends is covered the bitterness of described medicine and administration and do not postpone.The disclosed described compositions of the application mainly comprises the polymer of the sour solvable or swellable of uniting with lipid.The invention discloses the use in conjunction of lipid or lipid mixtures and pH dependent polymers, this pH dependent polymers is acid soluble or swellable.The composition and the preparation method of described polymer are disclosed among the patent application PCT/IN03/00390 of pending trial and the PCT/IN03/00392 in our previous submission.
Taste masking compositions and the application in multiple Pharmaceutical composition thereof of adopting synthetic sour soluble polymer are disclosed in patent application PCT/IN03/00390 and PCT/IN03/00392, this Pharmaceutical composition provides basically and has discharged immediately, and does not cause any delay that described active component absorbs.It is that effectively this peroral dosage form for example is oral liquid and solid dosage forms, as chewable tablet, dispersible tablet and quickly disintegrating tablet that being applied in of these polymer covered the taste aspect of desiring the described medicine that uses with peroral dosage form.The advantage of these polymer is that it does not dissolve and dissolve in acid pH in nearly neutral pH, make that the release under one's belt of described medicine is unaffected.
The type that depends on dosage form, the amount difference of giving the required polymer of palatability.The dosage of described active component also influences the performance of described polymer coating in addition.In some cases, when dosage is higher, need more amount of polymers so that effective coating to be provided.Need more homogenizing and more complete polymer coating to give the taste masking effect such as the liquid dosage form of dry syrup and suspension, and compare with the solid dosage forms of routine, the requirement of polymer is higher.
U.S. Patent application discloses the purposes of polymeric blends in taste masking that comprises with the sour soluble polymer of other pH dependent polymers or pH dependent/non-dependent combination with polymers for the 10/971st, No. 534.Described polymeric blends is used for reducing the amount at each polymer of mixture, so as to be in well by the safety of FDA defined every day allowance scope in, and the total amount of the described polymer in compositions is high enough to provide the taste masking effect.The total amount of described polymer and the preferred proportion of medicine are 0.5: 1-4: 1.The amount of disclosed polymer coating is for preventing that described medicine from being necessary in saliva or in the particulate aqueous medium leaching of the quilt that wraps that is used for recombinating.This compositions is useful for the medicine that has extensive absorption window along gastrointestinal tract and for discharging immediately of medicine and less than postponing.
What expect is to use minimum polymer to reach needed drug release rate.The difference of the present invention and prior art is that it has further reduced the amount of the polymer that is used to cover unpleasant taste.The invention discloses the purposes of lipid-polymeric matrix in taste masking is used, it has reduced the amount of needed polymer and lipid.Described medicine is 1 to the ratio of polymer: 0.1-1: 1.Compositions of the present invention cause described medicine almost immediately and rapid release.This have the compositions that discharges immediately fast for the described medicine of needs by fast Absorption to cause that the situation of therapeutical effect is useful early.Described compositions has also improved the bioavailability of medicament with the narrow absorption window that is limited to the upper stomach zone.The polymer of the acid soluble or swellable that uses in the described compositions comprises monomers methyl methacrylate, hydroxyethyl methylacrylate and the vinylpyridine that is respectively 50-75%, 15-35% and 5-15%w/w.
For utmost point bitter medicine thing is formulated as dry syrup or suspension, the protectiveness coating must be fully hydrophobic.Lipid is hydrophobic material thereby is widely used in this class application.But because its hydrophobic property, so postponed the release of medicine.In addition, it is very high providing the amount of the needed lipid of bitterness inhibitory action.The application of the lipid of higher load amount has further reduced rate of release.This has influenced bioavailability of medicament, especially has the bioavailability of medicament of the narrow absorption window that is confined to the upper stomach zone.
The invention discloses the lipid of using with the combination with polymers of acid soluble or swellable, this polymer dissolves and promotes the quick stripping of medicine fast in the pH of stomach.With described acid soluble/polymer of swellable introduces and guaranteed in the compositions that medicine discharges immediately from lipid-polymeric matrix.Not dissolving and prevent medicine leaching in the oral cavity in the pH of saliva of pH dependent polymers of the present invention.The lipid of using in compositions of the present invention is ester, aliphatic alcohol, hydrocarbon, neutral fat and the wax of fatty acid, fatty acid.Being suitable for lipid in the compositions of the present invention has usually and is higher than 40 ℃ fusing point.Described fatty acid or saturated or undersaturated.The satisfied fatty acid that uses in described compositions is long-chain (C 10-C 24) aliphatic carboxylic acid, as lauric acid, stearic acid and Palmic acid.Used lipid comprises aliphatic alcohol, as stearyl alcohol, palmityl alcohol and spermol, and preferred spermol.The fat of used fatty acid comprises the ester of glycerol and fatty acid, as glyceryl monostearate, monopalmitin, tripalmitin, docosane acid glyceride and castor oil hydrogenated, and preferred glyceryl monostearate and castor oil hydrogenated.
Another feature of the present invention is the application of mixture of the combination with polymers of described lipid and described acid soluble or swellable.The pH dependent polymers is 1 to the ratio of lipid in described compositions: 0.5-1: 40, preferred 1: 1-1: 35.Medicine is 1 to the ratio of lipid: 0.1-1: 8, preferred 1: 0.4-1: 6.The ratio of described medicine and pH dependent polymers is 1: 0.1-1: 1, preferred 1: 0.1-1: 0.6.
Described compositions also can be by the microencapsulation preparation of described medicine in described lipid-polymeric matrix.The microencapsulation of described medicine is finished in emulsifying, solvent evaporation or solvent extraction by described medicine and lipid-polymer solution or spray drying or the dispersion of medicine in lipid-polymer solution, preferably comes microencapsulation by solvent evaporation and spray drying technology.For the microencapsulation by solvent evaporation, preferred surfactants is a polyvinyl alcohol.It is preferred so that the mode that medicine, lipid and polymer all are dissolved in the solvent is selected described solvent.
In another feature of the present invention, obtain described Pharmaceutical composition in lipid-polymeric matrix by described medicine is dispersed in, this dispersion or by solidify through solvent evaporation, spray drying, spraying, the microencapsulation of melt granulation or realize by the tray dried method.The solvent of selecting for the described medicine of solubilising, lipid and polymer is a chlorinated hydrocabon, as dichloromethane and chloroform.
Can obtain the taste masking microgranule of described medicine by microencapsulation through the emulsified solvent evaporation technique.Decentralized photo is to contain the organic solvent that is dispersed or dissolved in the medicine in lipid-polymer solution, and disperse medium is a distilled water.Described lipid and polymer are dissolved in this organic solvent.Described medicine is added in this solution, then this organic facies is joined in the distilled water that contains polyvinyl alcohol (0.1%-1% weight ratio).At room temperature, the constant mechanical agitation speed with 500-1000rpm continues 2-3 hour.Make described solvent evaporation, and lyophilizing 5-10 hour by filtering the separation of particles that will obtain thus.
Perhaps, can obtain described composition grain by spray drying.Lipid and polymer are dissolved in the organic solvent.With described medicine or dissolving or be dispersed in this solution, and spray drying is to obtain the microgranule of taste masking.Dry gas can be such as the noble gas of nitrogen, argon and carbon dioxide or air.Preferred gas is air.The gas access temperature of spray dryer depends on the choice of Solvent of using, but can be 35 ℃-90 ℃, is preferably 35 ℃-75 ℃.Gas outlet temperature depends on solvent equally, but can be 25 ℃-75 ℃, is preferably 25 ℃-55 ℃.Described lipid and polymer are dissolved in dichloromethane or the chloroform, with described medicine or dissolving or be dispersed in this lipid-polymer solution.The resulting mixture of spray drying is to obtain microgranule.
Also can obtain taste masked particle of the present invention by in pallet, pouring into a mould chunk (slab).Lipid and polymer are dissolved in the organic solvent, with described medicine or dispersion or be dissolved in this lipid-polymer solution.Resulting solution is poured on the pallet with the described chunk of casting.With described solvent 25 ℃-30 ℃ down evaporations 2-3 hour, and by under vacuum, under 25 ℃-30 ℃ with dry 24 hours of described chunk to remove remaining solvent.With the exsiccant material gradation of institute and by 40 order mesh screens.
Lipid does not form good film, thereby the more substantial lipid of complete coating needs that only contains lipid fully is dispersed in this lipid matrix Shen with medicine.Because medicine need be dispersed in the described lipid matrix, so also need the lipid of a large amount of fusings such as melt granulation and the spraying technology of solidifying.Compare with the amount of the lipid of using among other embodiment disclosed by the invention, need a large amount of lipid to come dispersion medicine in the process of melt granulation, this can needed lipid take temperature out from embodiment 5 and embodiment 9.Another feature of the present invention is to use the lipid aggregate thing solution in the solvent to reduce with the amount that medicine is dispersed in this lipid aggregate thing substrate, makes the lipid that needs in described compositions.
Also can obtain taste masked particle of the present invention by melt granulation.Lipid is placed in the strap clamp sleeve containes that is connected with circulator bath.The temperature of recirculated water is set, is higher than under 3 ℃-5 ℃ of the fusing points so that this lipid remains on.Under agitation with polymer dispersed in the lipid of this fusing, add medicine subsequently.The temperature that little by little reduces recirculated water is to cool off the lipid of this fusing.With the screening of the solid matter that obtains thus and by 40 order mesh screens.
Compare with other compositions that adopts a small amount of lipid and described combination with polymers, example as shown in embodiment 5 and embodiment 9, medicine discharges slower from the compositions of the lipid that contains the higher load amount.
Taste masked particle that obtains among the present invention and particulate can with such as natural or artificial perfume, citric acid and tartaric flavoring agent, such as the sweeting agent of sucrose, glucide and aspartame (aspartame), and other medicines can be accepted mixed with excipients to be mixed with conventional tablet, chewable tablet or dispersible tablet, dry syrup, suspension, wafer or any other suitable peroral dosage form.Taste masked particle that obtains in the present invention and particulate can comprise the polymer of acid soluble or swellable and the mixture of lipid, and the reorganization medium of available pH＞3.5 carries out suspendible.
Also (can be used as Ceftum buys the disclosure from comprising the particulate dry syrup product of the cefuroxime axetil with complete stearic acid coating with medicine, by Glaxo WellcomeOperations Harmire Road, Barnard Castle County Durham, DL 12 8DT, UK produces, and is sold by Glaxo India Limited) in release compare with release from compositions of the present invention.Compare with the intestinal zone, cefuroxime axetil is absorbed in the upper stomach zone better.People such as Dantzig (Anne H.Dantzig, Dale C.Duckworth, Linda B.Tabas, Biochimica et Biophysica Acta 1191,1994,7-13) show that cefuroxime axetil is a cefuroxime by esterase hydrolyzed, has reduced the concentration of cefuroxime axetil in enteric cavity in enteric cavity, cause absorbing and reduce, make cefuroxime axetil in human body, have lower bioavailability.Cefuroxime axetil has had only the bioavailability of 32-50%.Therefore any reason owing to the preparation aspect all should minimize declined bioavailability of oral administration.Therefore, the 0.07N HCl (monograph of American Pharmacopeia 26) that is used for the dissolution medium of cefuroxime axetil tablet carries out the stripping of this commercially available prod as medium in acid pH.
In the stripping that is equivalent to contain on the heavy 4.18g sample (41.8g/50ml, 5ml are equivalent to the cefuroxime of 125mg) of 125mg dose the Ceftum sample of cefuroxime axetil.With the moistening in the dissolution medium that from the 900ml medium, takes out of described sample, and then place the stripping container.The glass beaker that is used for this sample of moistening was used the excessive flushing of dissolution medium of taking out before stripping, and this dissolution medium is placed the stripping container once more.Under 37 ± 0.5 ℃, adopt USP II type instrument with the 100rpm rotation, in the buffer medium of the 0.07N hydrochloric acid that contains 900ml, measure the release of cefuroxime axetil.In the time of 30,60,120,180 and 240 minutes, take out sample.Each amount of taking out is replaced to keep sink conditions with fresh medium.The medication amount that discharged in the time of 30 minutes is 77.17% when being 69.5% and 240 minute when being 64.6%, 180 minute when being 50%, 120 minute when being 40%, 60 minute.
Embodiment 1 and embodiment 2 disclose the method for the polymer for preparing acid soluble/swellable.Illustrational as institute among the embodiment 3-9, the following taste masking Pharmaceutical composition that provides has been measured drug release with time correlation.With the moistening in the dissolution medium that from the 900ml medium, takes out of described sample, and then place the stripping container.The glass beaker that is used for this sample of moistening was used the excessive flushing of dissolution medium of taking out before stripping, and should place the stripping container once more by molten mountain medium.
In the time of 37 ± 0.5 ℃, use USP II type instrument, the release of test cephalo furan XINYI acyl-oxygen ethyl ester from taste masked particle in the 0.07N of 900ml hydrochloric acid with the 100rpm rotation.In the time of 30,60,120,180 and 240 minutes, take out sample.Each amount of taking out is replaced to keep sink conditions with fresh medium.
In the time of 37 ± 0.5 ℃, use USP II type instrument, the release of test ciprofloxacin from taste masked particle in the 0.01N of 900ml hydrochloride buffer with the 100rpm rotation.In the time of 30,60,120,180 and 240 minutes, take out sample.Each amount of taking out is replaced to keep sink conditions with fresh medium.Pharmaceutical composition of the present invention has been covered the bitterness of medicine, does not discharge described medicine in the pH of saliva, but discharges this medicine and not delay in the pH of stomach, and insoluble in water.
With reference to following illustrative non-limiting example described taste masking compositions and characteristic thereof are described.
Embodiment 1
The polymer that synthesizes acid soluble or swellable by solution polymerization process.Hydrophobic monomer, alkaline monomer and optional hydrophilic monomer are dissolved in the solvent dimethylformamide.Described polymer has following monomer and forms: the hydroxyethyl methylacrylate of the methyl methacrylate of 65% weight ratio, 24% weight ratio and the vinylpyridine of 11% weight ratio.With azo initiator, azodiisobutyronitrile joins in this monomeric dimethyl formamide solution.With nitrogen to the reactant mixture purging so that inert atmosphere to be provided.By this reactant mixture being heated to 65 ℃ and keep finishing in 18 hours polyreaction.The synthetic polymer of institute reclaims by precipitate in non-solvent (be water) herein, and under vacuum in the time of 45 ℃ drying.The molecular weight of synthetic polymer is measured with the Waters gel permeation chromatography, adopts styragel (Styragel) post, with polystyrene standards (U.S. Polysciences company) as reference.The molecular weight of this polymer is 53,000.
Embodiment 2
The polymer that synthesizes acid soluble or swellable by solution polymerization process.Hydrophobic monomer, alkaline monomer and optional hydrophilic monomer are dissolved in the solvent dimethylformamide.Described polymer has following monomer and forms: the hydroxyethyl methylacrylate of the methyl methacrylate of 73% weight ratio, 18% weight ratio and the vinylpyridine of 9% weight ratio.With azo initiator, azodiisobutyronitrile joins in this monomeric dimethyl formamide solution.With nitrogen to the reactant mixture purging so that inert atmosphere to be provided.By this reactant mixture being heated to 65 ℃ and keep finishing in 18 hours polyreaction.The synthetic polymer of institute reclaims by precipitate in non-solvent (be water) herein, and under vacuum in the time of 45 ℃ drying.The molecular weight of synthetic polymer is measured with the Waters gel permeation chromatography, adopts styragel (Styragel) post, with polystyrene standards (U.S. Polysciences company) as reference.The molecular weight of this polymer is 52,000.
Embodiment 3
Medicine dissolution in the organic solvent solution of lipid and polymer, and is obtained containing the microgranule of this medicine by the evaporation of microencapsulation in water and described organic solvent, thereby obtain the taste masking compositions.
Lipid-polymer solution: table 1 has shown the compositions that contains various lipid-polymeric blends.The acid soluble polymer of preparation among the embodiment 1 is used as one of pH dependent polymers in whole compositionss.Used quantity of solvent is the chlorinated hydrocabon such as chloroform and dichloromethane of 7ml.The amount of lipid and polymer is shown in the table 1.
Obtain the taste masking microgranule by the emulsified solvent evaporation technique.Cefuroxime axetil is dissolved in the lipid-polymer solution of the solvent preparation of using necessary amount.Lipid-the polymer solution that will contain this medicine under mechanical agitation dropwise joins in the distillation water-bath.The polyvinyl alcohol of 0.1% weight ratio is joined in this distilled water to promote this to contain the dispersion of the lipid-polymer solution of medicine.At room temperature, the constant mechanical agitation speed with 500rpm continues 3-4 hour.With solvent evaporation, by filtering to isolate resulting microgranule, and lyophilization 7 hours.Monitor the drug release pattern of prepared compositions, the results are shown in Table 2 with described.
Table 1
Series number Lipid The pH dependent polymers Medicine
1 Stearic acid 0.45g Acid soluble polymer 0.15g Cefuroxime axetil 0.3g
2 Palmic acid 0.50g Acid soluble polymer 0.3g Cefuroxime axetil 0.6g
3 Spermol 0.40g Acid soluble polymer 0.2g Cefuroxime axetil 0.6g
Table 2
Series number Compositions The medicine % that in 30 minutes, discharges
1 The acid soluble polymer 0.15g of stearic acid 0.45g cefuroxime axetil 0.3g 98.0
2 The acid soluble polymer 0.3g of Palmic acid 0.50g cefuroxime axetil 0.6g 99.6
3 The acid soluble polymer 0.2g of spermol 0.4g cefuroxime axetil 0.6g 96.8
Embodiment 4
The chunk that contains the lipid-polymer of medicine by cast prepares the taste masking compositions.The organic solvent solution that will contain the lipid-polymer of the medicine that exists with the solution form or with discrete form is cast on the pallet.Make solvent evaporation, carry out gradation with described by 40 order mesh screens and obtain granule.
Lipid-polymer solution: table 3 has shown the compositions that contains various lipid-polymeric blends.The acid soluble polymer of preparation among the embodiment 1 is used as one of pH dependent polymers in whole coated compositions.Used quantity of solvent is the chlorinated hydrocabon such as chloroform and dichloromethane of 7ml.The amount of lipid and polymer also is shown in the table 3.
By the granule of described preparation of gradation taste masking, this piece is obtained by lipid-polymer solution that cast contains the medicine that exists with discrete form.Ciprofloxacin is joined in the chloroformic solution with the lipid-polymer of the solvent of necessary amount preparation.Lipid-the polymer solution that will contain this medicine is poured on the pallet to pour into chunk.Under 25 ℃ with solvent evaporation 2-3 hour.Removed residual solvent in 24 hours by under 25 ℃, in a vacuum described compositions being placed.Monitor the drug release pattern of prepared compositions, the results are shown in Table 4 with described.
Table 3
Series number Lipid The pH dependent polymers Medicine
1 Stearic acid 0.844g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
2 Palmic acid 0.844g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
3 Spermol 0.844g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
4 Palmic acid 0.422g stearic acid 0.422g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
5 Stearic acid 0.422g spermol 0.422g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
Table 4
Series number Compositions The medicine % that discharges (minute)
30 60 120 180
1 The acid soluble polymer 0.1g of stearic acid 0.844g ciprofloxacin 0.583g 83.8 87.7 88.0 93.3
2 The acid soluble polymer 0.10g of Palmic acid 0.844g ciprofloxacin 0.583g 91.5 95.0 96.2 98.0
3 The acid soluble polymer 0.1g of spermol 0.844g ciprofloxacin 0.583g 91.1 92.4 94.2 95.0
4 The acid soluble polymer 0.1g of Palmic acid 0.422g stearic acid 0.422g ciprofloxacin 0.583g 88.8 90.8 92.0 93.0
5 The acid soluble polymer 0.1g of spermol 0.422g stearic acid 0.422mg 82.5 90.0 94.3 97.3
Ciprofloxacin 0.583g
Embodiment 5
Obtain the granule of taste masking by the melt granulation method.Lipid is placed in the container of the strap clamp cover that is connected with circulator bath.The temperature of recirculated water is set, is higher than 3 ℃-5 ℃ of its fusing points so that this lipid remained on.The acid soluble polymer of preparation among the embodiment 2 is used for said composition.Under agitation with this polymer dispersed the fusing lipid in, add ciprofloxacin subsequently.The temperature that reduces recirculated water gradually is to cool off the lipid of this fusing.Employing is sieved the solid matter that is obtained by 40 order mesh screens.Be displayed in Table 5 the compositions that contains various lipid-mixture of polymers.Monitor the drug release pattern of prepared compositions, with the results are shown in Table 6.
Table 5
Series number Lipid The pH dependent polymers Medicine
1 Stearic acid 1.75g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
2 Palmic acid 0.873g stearic acid 0.873g Acid soluble polymer 0.10g Ciprofloxacin 0.583g
Table 6
Series number Compositions The medicine % that discharges (minute)
30 60 120 180 240
1 The acid soluble polymer 0.1g of stearic acid 1.75g ciprofloxacin 0.583g 69.8 77.5 84.5 87.0 94.7
2 The acid soluble polymer 0.1g of Palmic acid 0.873g stearic acid 0.873g ciprofloxacin 0.583g 70.5 75.4 80.0 84.0 92.0
Embodiment 6
Obtain the taste masking microgranule by spray drying.Described lipid and polymer are dissolved in the organic solvent, and with medicine or dissolving or be dispersed in this solution, spray drying is to obtain described taste masking microgranule.Dry gas can be such as the noble gas of nitrogen, argon and carbon dioxide or air.Preferred in the present invention gas is air.The gas access temperature of spraying is 350 ℃-750 ℃.Gas outlet temperature is 350 ℃-55 ℃.Lipid and polymer are dissolved in the chloroform, and cefuroxime axetil is dissolved in this lipid-polymer solution.The acid soluble polymer of preparation among the embodiment 1 is used for compositions.The gained mixture carries out spray drying to obtain described microgranule.Be displayed in Table 7 the compositions that contains various lipid-mixture of polymers.Monitor the drug release pattern of prepared compositions, with the results are shown in Table 8.
Table 7
Series number 1 Lipid stearic acid 3.0g The acid soluble polymer 1.0g of pH dependent polymers Medicine cefuroxime axetil 3.0g
2 Stearic acid 1.5g Palmic acid 1.5g Acid soluble polymer 1.0g Cefuroxime axetil 3.0g
3 Stearic acid 2.0g glyceryl monostearate 1.0g Acid soluble polymer 1.0g Cefuroxime axetil 3.0g
4 Stearic acid 2.0g castor oil hydrogenated 1.0g Acid soluble polymer 1.0g Cefuroxime axetil 3.0g
Table 8
Series number Compositions The medicine % that discharges (minute)
30 60 120 l80
1 The acid soluble polymer 0.1g of stearic acid 3.0g cefuroxime axetil 3.0g 70.7 81.0 92.6 93.2
2 Palmic acid 1.5g 87.4 95.1 98.4 -
The acid soluble polymer 1.0g of stearic acid 1.5g cefuroxime axetil 3.0g
3 The acid soluble polymer 1.0g of stearic acid 2.0g glyceryl monostearate 1.0g cefuroxime axetil 3.0g 96.5 97.5 98.0 -
4 The acid soluble polymer 0.1g of stearic acid 2.0g castor oil hydrogenated 1.0g cefuroxime axetil 3.0g 73.3 81.2 91.4 97.0
Embodiment 9
Obtain taste masked particle by the melt granulation method.Lipid is placed in the container of the strap clamp cover that is connected with circulator bath.The temperature of recirculated water is set, is higher than 3 ℃-5 ℃ of its fusing points so that this lipid remained on.The acid soluble polymer of preparation among the embodiment 2 is used for said composition.Under agitation with this polymer dispersed the fusing lipid in, add cefuroxime axetil subsequently.The temperature that reduces recirculated water gradually is to cool off the lipid of this fusing.Employing is sieved the solid matter that is obtained by 40 order mesh screens.Be displayed in Table 9 the composition that contains various lipid-mixture of polymers.Monitor the drug release pattern of prepared compositions, with the results are shown in Table 10.
Table 9
Series number Lipid The pH dependent polymers Medicine
1 Stearic acid 3.6g Acid soluble polymer 0.150g Cefuroxime axetil 0.9g
2 Spermol 2.3g Acid soluble polymer 0.150g Cefuroxime axetil 0.90g
3 Palmic acid 1.2g stearic acid 1.2g Acid soluble polymer 0.200g Cefuroxime axetil 0.450g
4 Lauric acid 2.4g Acid soluble polymer 0.2g Cefuroxime axetil 0.45g
5 Palmic acid 2.4g Acid soluble polymer 0.2g Cefuroxime axetil 0.450g
Table 10
Series number Compositions The medicine % time that discharges (minute)
30 60 120 180 240
1 The acid soluble polymer 0.15g of stearic acid 3.6g cefuroxime axetil 0.9 g 55.4 61.0 65.0 71．O 73．O
2 The acid soluble polymer 0.15g of spermol 2.3g cefuroxime axetil 0.9 g 54.7 64.6 70.0 78．0 81．5
3 The acid soluble polymer 0.200g of Palmic acid 1.2g stearic acid 1.2g cefuroxime axetil 0.450g 53.6 58.7 62.0 68．O 72．0
4 The acid soluble polymer 0.2g of lauric acid 2.4g cefuroxime axetil 0.45g 62.4 64.5 70.0 77．13 82．2
5 The acid soluble polymer 0.2g of Palmic acid 2.4g cefuroxime axetil 0.450g 55.3 62.0 65.0 73．3 78．0
Advantage of the present invention is as follows:
1. the composition of the present invention's description comprises anti-enteron aisle polymer (reverse enteric polymer) or the acid soluble polymer of uniting with lipid or lipid mixture, this polymer promotes medicine to discharge fast in the pH of stomach, and reduces required polymer total amount with respect to the medicine in the said composition.
2. known aliphatic acid can be used for the taste masking purposes, but for complete drug coated, needs a large amount of aliphatic acid, but because they are hydrophobic, has postponed again the release of medicine. The invention discloses the application of pH dependence polymer, this pH dependence polymer keeps shrinkage in the pH of saliva, thereby is used for synergistically the inhibition of taste. But this polymer dissolves when stomach pH, and discharges a large amount of medicines and without any delay.
3. the invention discloses the common application of acid soluble polymer and lipid, wherein this polymer in water and also o'clock keeps shrinkage in pH＞3.5. These preparations are better than adopting the composition of the mixture of water-soluble polymer and lipid, and the latter is not suitable for liquid oral medicine.
4. the common application of acid soluble polymer and aliphatic acid helps the taste masking effect of acquisition when the aliphatic acid that hangs down load capacity and polymer. Use lipid aggregate thing solution so that described medicine is dispersed in this lipid-polymer substrate, further reduced the amount of in composition, covering the needed lipid of medicine bitter taste.
5. the application of acid soluble polymer in composition helps medicine to discharge in the acid pH of stomach and do not postpone, and this polymer does not discharge medicine in the pH of saliva in addition. Therefore be different from the composition that adopts lipid and the combination of pH dependent/non-dependent polymer and enteric polymer, composition of the present invention provide immediately and also be close to completely medicine release.
6. the acid soluble polymer that uses does not in the present invention show any negative interaction with the medicine cefuroxime axetil, and this situation is presented at by in the anti-enteric coating materials that comprises the dimethyl amino ethyl methacrylate that is similar to Eudragit E. Therefore the composition of the present invention that comprises described lipid-polymer substrate is applicable to show the medicine that negative interaction is arranged with Eudragit E.
7. kept the purposes of the acid soluble polymer of shrinkage to be that it provides larger adaptability for the taste masking composition such as dry syrup or suspension composite at pH greater than 3.5 o'clock, these compositions need to be recombinated more than or equal to 3.5 o'clock at pH, therefore different from the system that introduces anti-enteron aisle polymer Eudragit E, should be Eudragit E and up to pH 5.5 time, show swelling.
With based on by independent stearic acid the burst size that medicine carries out the commercial composite Ceftm of complete lipid dressing being compared, in this composition, adopt the composition of described acid soluble polymer to discharge more quickly described medicine. In the situation of bitter drug cefuroxime axetil, this is favourable, because it can be absorbed from territory, gastric area, top better.

Claims (49)

1. the Pharmaceutical composition that comprises medicine, lipidic component and pH dependent polymers, wherein said pH dependent polymers are acid soluble or swellable and have formula: P[A (x)B (y)C (z)], wherein P is for comprising (A) hydrophobic monomer, (B) alkaline monomer and (C) polymer of hydrophilic monomer, and (x)=30% to 95%, (y)=5% to 70%, (z)=0% to 60%, all percentage ratios are all represented with w/w, so that x+y+z=100%.
2. compositions as claimed in claim 1, wherein said pH dependent polymers is selected from the polymer of acid soluble polymer or sour swellable.
3. compositions as claimed in claim 1, the polymer of wherein said acid soluble or swellable by be respectively 50% to 75%, 15% to 35% and about monomers methyl methacrylate of 5% to 15%w/w, hydroxyethyl methylacrylate and vinylpyridine form.
4. compositions as claimed in claim 1, wherein said lipidic component are selected from ester, aliphatic alcohol, hydro carbons, neutral fat and the wax of fatty acid, fatty acid.
5. compositions as claimed in claim 4, wherein said fatty acid is selected from saturated or unsaturated fatty acid.
6. compositions as claimed in claim 5, wherein said saturated fatty acid comprises the long chain aliphatic carboxylic acid that is selected from lauric acid, stearic acid and Palmic acid.
7. compositions as claimed in claim 4, wherein said aliphatic alcohol comprises the long chain aliphatic that is selected from stearyl alcohol, palmityl alcohol and spermol.
8. compositions as claimed in claim 4, wherein said aliphatic alcohol are spermol.
9. compositions as claimed in claim 4, the ester of wherein said fatty acid comprises the ester of glycerol and fatty acid, and is selected from glyceryl monostearate, monopalmitin, tripalmitin, docosane acid glyceride and castor oil hydrogenated.
10. compositions as claimed in claim 4, the ester of wherein said fatty acid is selected from glyceryl monostearate and castor oil hydrogenated.
11. compositions as claimed in claim 1, wherein said lipidic component is used with the combination of single lipid or lipid.
12. compositions as claimed in claim 1, wherein the pH dependent polymers is 1: 0.5 to 1: 40 to the ratio of lipidic component.
13. compositions as claimed in claim 1, wherein the pH dependent polymers is 1: 1 to 1: 35 to the ratio of lipidic component.
14. compositions as claimed in claim 1, its Chinese medicine is 1: 0.1 to 1: 8 to the ratio of lipid.
15. compositions as claimed in claim 1, its Chinese medicine is 1: 0.4 to 1: 6 to the ratio of lipid.
16. compositions as claimed in claim 1, its Chinese medicine is 1: 0.1 to 1: 1 to the ratio of pH dependent polymers.
17. compositions as claimed in claim 1, its Chinese medicine is 1: 0.1 to 1: 0.6 to the ratio of pH dependent polymers.
18. compositions as claimed in claim 1, wherein said medicine is used with itself or with the form of the acceptable salt of its medicine or ester or amide.
19. compositions as claimed in claim 1, wherein said medicine be selected from macrolide antibiotics, fluoroquinolones, cephalosporins, nonsteroidal anti-inflammatory analgesic medicine, cox 2 inhibitor, antihistaminic, comprise the oxazolidine ketone and the dextromethorphan of Linezolid, wherein said macrolide antibiotics is selected from erythromycin, azithromycin and clarithromycin again; Described fluoroquinolones is selected from ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin again; Described cephalosporins is selected from cefuroxime, cefaclor, cephalexin, cefadroxil, Cefpodoxime Proxetil again; The anti-inflammatory analgesic medicine of described nonsteroidal is selected from ibuprofen, aspirin, acetaminophen and diclofenac sodium again; Described COX2 inhibitor is selected from etoricoxib and celecoxib again; Described antihistaminic is selected from cimetidine, ranitidine, famotidine and chlorphenamine maleate again.
20. compositions as claimed in claim 1, wherein said compositions are particle form, described medicine is dispersed in the polymer-lipid substrate.
21. compositions as claimed in claim 1, wherein said compositions comprise the granule of himself or comprise the medicine acceptable forms.
22. compositions as claimed in claim 1, wherein said compositions are the drink form that is selected from dry syrup and suspension.
23. compositions as claimed in claim 1, wherein said compositions are the solid dosage forms that is selected from chewable tablet, effervescent tablet, quickly disintegrating tablet and dispersible tablet.
24. preparation comprises the method for the Pharmaceutical composition of medicine, lipidic component and pH dependent polymers, wherein said pH dependent polymers is acid soluble or swellable and has formula: P[A (x)B (y)C (z)], wherein P is for comprising (A) hydrophobic monomer, (B) alkaline monomer and (C) polymer of hydrophilic monomer, and (x)=30% to 95%, (y)=5% to 70%, (z)=0% to 60%, all percentage ratios are all represented with w/w, so that x+y+z=100%, wherein said method comprises by being selected from technology that microencapsulation, spray drying, melt granulation, tray dried method and spraying solidify and described medicine is disperseed or is coated in the substrate of described polymer and lipidic component.
25. method as claimed in claim 24, wherein said method comprises the microencapsulation that adopts the emulsified solvent method of evaporating, described microencapsulation is undertaken by following steps: described polymer and lipid are dissolved in the organic solvent that is selected from chloroform and dichloromethane to form lipid-polymer solution, described medicine is joined in the described solution to form organic facies, described organic facies is dispersed in the distilled water of the polyvinyl alcohol that contains 0.1% to 1%w/w amount, under 25 ℃ to 30 ℃ temperature, described mixture with the speed of about 500rpm to 1000rpm mechanical agitation 2-3 hour continuously, was separated the microgranule that obtains after filtration and the described granule of lyophilizing 5 hours to 10 hours then.
26. method as claimed in claim 24, wherein said method comprises carries out gradation with contain the described polymer of described medicine and the dichloromethane of lipid or the chunk of chloroformic solution cast with dissolving or discrete form, and removes described solvent by evaporation under 25 ℃ to 30 ℃.
27. method as claimed in claim 24, wherein under agitation reach and keep temperature to be higher than under the condition of 3 ℃-5 ℃ of lipid fusing points, described polymer and described medicine are dispersed in the lipid of fusing to obtain the material of fusing, material with described fusing little by little cools off to obtain granule then, subsequently with described particle screening.
28. method as claimed in claim 24, wherein said method comprises and will contain the described lipid-polymer solution spray drying of described medicine to obtain microgranule, described microgranule is dried in the presence of dry gas subsequently, and described dry gas is selected from nitrogen, argon, carbon dioxide and air.
29. method as claimed in claim 28, wherein said dry gas are air.
30. method as claimed in claim 24, wherein said pH dependent polymers is selected from the polymer of acid soluble polymer or sour swellable.
31. method as claimed in claim 24, the polymer of wherein said acid soluble or swellable by be respectively 50% to 75%, 15% to 35% and about monomers methyl methacrylate of 5% to 15%w/w, hydroxyethyl methylacrylate and vinylpyridine form.
32. method as claimed in claim 24, wherein said lipidic component are selected from ester, aliphatic alcohol, hydro carbons, neutral fat and the wax of fatty acid, fatty acid.
33. method as claimed in claim 32, wherein said fatty acid is selected from saturated or unsaturated fatty acid.
34. method as claimed in claim 33, wherein said saturated fatty acid comprises the long chain aliphatic carboxylic acid that is selected from lauric acid, stearic acid and Palmic acid.
35. method as claimed in claim 32, wherein said aliphatic alcohol comprises the long chain aliphatic that is selected from stearyl alcohol, palmityl alcohol and spermol.
36. method as claimed in claim 32, wherein said aliphatic alcohol are spermol.
37. method as claimed in claim 32, the ester of wherein said fatty acid comprises the ester of glycerol and fatty acid, and is selected from glyceryl monostearate, monopalmitin, tripalmitin, docosane acid glyceride and castor oil hydrogenated.
38. method as claimed in claim 32, the ester of wherein said fatty acid is selected from glyceryl monostearate and castor oil hydrogenated.
39. method as claimed in claim 24, wherein said lipidic component is used with the combination of single lipid or lipid.
40. method as claimed in claim 24, wherein the pH dependent polymers is 1: 0.5 to 1: 40 to the ratio of lipidic component.
41. method as claimed in claim 24, wherein the pH dependent polymers is 1: 1 to 1: 35 to the ratio of lipidic component.
42. method as claimed in claim 24, its Chinese medicine is 1: 0.1 to 1: 8 to the ratio of lipid.
43. method as claimed in claim 24, its Chinese medicine is 1: 0.4 to 1: 6 to the ratio of lipid.
44. method as claimed in claim 24, its Chinese medicine is 1: 0.1 to 1: 1 to the ratio of pH dependent polymers.
45. method as claimed in claim 24, its Chinese medicine is 1: 0.1 to 1: 0.6 to the ratio of pH dependent polymers.
46. method as claimed in claim 24, wherein said medicine is used with itself or with the form of the acceptable salt of its medicine or ester or amide.
47. method as claimed in claim 24, wherein said medicine be selected from macrolide antibiotics, fluoroquinolones, cephalosporins, nonsteroidal anti-inflammatory analgesic medicine, cox 2 inhibitor, antihistaminic, comprise the oxazolidine ketone and the dextromethorphan of Linezolid, wherein said macrolide antibiotics is selected from erythromycin, azithromycin and clarithromycin again; Described fluoroquinolones is selected from ciprofloxacin, enrofloxacin, ofloxacin, Gatifloxacin, levofloxacin and norfloxacin again; Described cephalosporins is selected from cefuroxime, cefaclor, cephalexin, cefadroxil, Cefpodoxime Proxetil again; The anti-inflammatory analgesic medicine of described nonsteroidal is selected from ibuprofen, aspirin, acetaminophen and diclofenac sodium again; Described COX2 inhibitor is selected from etoricoxib and celecoxib again; Described antihistaminic is selected from cimetidine, ranitidine, famotidine and chlorphenamine maleate again.
48. method as claimed in claim 24, wherein said compositions are particle form, described medicine is dispersed in the polymer-lipid substrate.
49. method as claimed in claim 24, wherein said compositions comprise the granule of himself or comprise the medicine acceptable forms.
CNB2004800430930A 2004-12-10 2004-12-10 Improve Pharmaceutical composition of palatability of drugs and preparation method thereof Expired - Fee Related CN100548270C (en)

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WO2009000132A1 (en) * 2007-06-23 2008-12-31 Pficker Pharmaceuticals Ltd. Immediate release effervescent-formulation and preparing process thereof
CN104640537A (en) * 2012-09-18 2015-05-20 麦克内尔-Ppc股份有限公司 Low melting propionic acid derivative particles for use in oral dosage forms
CN106727337A (en) * 2016-12-13 2017-05-31 河南后羿实业集团有限公司 A kind of Enrofloxacin soluble powder and preparation method thereof

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JP5563841B2 (en) * 2010-02-05 2014-07-30 沢井製薬株式会社 Oral pharmaceutical composition masking unpleasant taste of drug
US11896037B2 (en) * 2016-08-03 2024-02-13 Temple University-Of The Commonwealth System Of Higher Education Microencapsulation of active agents

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009000132A1 (en) * 2007-06-23 2008-12-31 Pficker Pharmaceuticals Ltd. Immediate release effervescent-formulation and preparing process thereof
CN104640537A (en) * 2012-09-18 2015-05-20 麦克内尔-Ppc股份有限公司 Low melting propionic acid derivative particles for use in oral dosage forms
CN106727337A (en) * 2016-12-13 2017-05-31 河南后羿实业集团有限公司 A kind of Enrofloxacin soluble powder and preparation method thereof

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AU2004325469A1 (en) 2006-06-15
WO2006061846A1 (en) 2006-06-15
BRPI0419125A (en) 2007-12-11
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