WO2011124876A2 - Comprimé lyophilisé - Google Patents

Comprimé lyophilisé Download PDF

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Publication number
WO2011124876A2
WO2011124876A2 PCT/GB2011/000502 GB2011000502W WO2011124876A2 WO 2011124876 A2 WO2011124876 A2 WO 2011124876A2 GB 2011000502 W GB2011000502 W GB 2011000502W WO 2011124876 A2 WO2011124876 A2 WO 2011124876A2
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WO
WIPO (PCT)
Prior art keywords
tablet
freeze
drug
particles
binder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2011/000502
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English (en)
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WO2011124876A3 (fr
Inventor
Afzal Mohammed
Farhan Alhusban
Yvonne Perrie
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Aston University
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Aston University
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Filing date
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Publication of WO2011124876A3 publication Critical patent/WO2011124876A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a freeze-dried tablet and its method of manufacture.
  • Swallowing difficulty or dysphasia affects a significant proportion of people, particularly in the geriatric and paediatric populations.
  • orally disintegrating tablets have been developed.
  • Orally disintegrating tablets are solid unit dosage forms that disintegrate or dissolve in the mouth without chewing or the need for added water. Typically, the tablets remain solid until administered. However, once in the mouth, the tablets transform into a liquid within a short period of time,
  • the pharmaceutically active agent may be dry-mixed with one or more excipients and the resulting mixture compressed to form a tablet.
  • the tablet may be produced by freeze-drying a suspension or solution of the pharmaceutically active agent and excipients.
  • active agent not all forms are suitable for freeze-drying .
  • some active agents take the form of pellets or particles that are too dense to be adequately suspended in conventional freeze-drying media for the duration of the freeze-drying process.
  • Microparticles are known in the field of drug delivery and have been used to provide controlled or sustained release of a drug. Typically, these microparticles comprise drug(s) in combination with polymers that modify the rate of release of the drug(s), protect the drug(s) from undergoing
  • microparticles may each comprise a drug-containing core encapsulated or coated by one or more layers of a rate- controlling polymer (s).
  • the polymer layer (s) may be selected to provide extended, delayed or pulsed drug delivery, allowing the rate of release of the drug to be tailored as required.
  • the microparticles may each comprise a drug-containing core surrounded by an enteric coating.
  • Such coatings are stable under the highly acidic pH conditions of the stomach. However, under the less acidic conditions of the small intestine, the coatings degrade rapidly, allowing the drug to be released and absorbed in the small intestine. By targeting the release of the drug in this manner, the drug is protected from the highly acidic
  • Drug microparticles can be administered in tablet form.
  • the microparticles are typically mixed with excipients and compressed.
  • the microparticles are typically mixed with excipients and compressed.
  • a freeze-dried tablet comprising
  • particles comprising one or more drugs
  • a binder comprising a proteinaceous material
  • a viscosity modifying agent comprising a polysaccharide
  • a method of manufacturing the tablet above which comprises:
  • a suspension of particles comprising one or more drugs in a medium comprising (i) the binder comprising a proteinaceous material, (ii) the viscosity modifying agent comprising a polysaccharide and (iii) a solvent,
  • a binder comprising a proteinaceous material, (ii) a viscosity modifying agent comprising a polysaccharide and (iii) a solvent.
  • proteinaceous material interacts with the polysaccharide to form a polymer network that allows the particles to be
  • the polysaccharide e.g. carrageenan
  • the proteinaceous material e.g. gelatin
  • these oppositely charged species form coacervates and gel to provide a suspending medium with desirable
  • the drug particles remain suspended in the medium during the freezing step, allowing the suspension to be lyophilized to form the tablet.
  • the associative interaction between the proteinaceous material and the polysaccharide allows relatively high
  • viscosities to be achieved even at relatively low binder (e.g. proteinaceous material) and/or viscosity modifying agent (e.g. polysaccharide) concentrations.
  • binder e.g. proteinaceous material
  • viscosity modifying agent e.g. polysaccharide
  • the tablet of the present invention is preferably an orally disintegrating tablet. Such tablets disintegrate in the mouth without the need for chewing and/or the need for added water.
  • the binder and viscosity modifying agent provide the tablet with sufficient structural integrity, so that it can be stored and administered in solid form. However, once in contact with saliva in the oral cavity, the freeze-dried tablet dissolves and/or disintegrates, allowing the particles of the drug to be swallowed by the patient.
  • the freeze-dried tablet is an orally
  • Guidance, orally disintegrating tablets are considered to be solid oral preparations which disintegrate rapidly in the oral cavity with an in vivo disintegration time of approximately 30 seconds or less, when based on the USP disintegration test method or alternative (see http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatorylnformation/Guidances/ucm070578. pdf) and USP 29, ⁇ 701> Disintegration, pp. 2670-2672.
  • the freeze-dried tablet of the present invention is an orally disintegrating tablet that dissolves and/or disintegrates in the mouth of a user in less than 20 seconds, less than 15 seconds, less than 10 seconds, or more preferably less than 5 seconds.
  • the binder employed in the present invention is a proteinaceous material.
  • the binder and, in particular, the proteinaceous material is preferably water- soluble and/or has a glass transition temperature close or at body temperature to facilitate disintegration. Suitable glass transition temperatures range from, for example, 35 to 38 degrees C, preferably about 37 degrees C. Suitable
  • proteinaceous materials include fibroin, elastin, keratin, a collagen-based polymer and combinations thereof.
  • the proteinaceous material is a
  • collagen-based polymer such as gelatin.
  • Low bloom strength gelatin, high bloom strength gelatin or a combination thereof may be used.
  • low bloom strength gelatin is
  • the binder and, in particular, the proteinaceous material forms 20 to 45 weight %, more
  • the freeze-dried tablet comprises gelatin in an amount of 20 to 45 weight %, preferably 30 to 40 weight % of the freeze-dried tablet.
  • the viscosity modifying agent employed in the present invention is a polysaccharide.
  • the viscosity modifying agent and, in particular, the polysaccharide is preferably water- soluble and/or has a glass transition temperature close or at body temperature to facilitate disintegration. Suitable glass transition temperatures range from, for example, 35 to 38 degrees C, preferably about 37 degrees C. Suitable
  • polysaccharides include carrageenan, agar, maltodextrin, pectin and alginate.
  • the viscosity modifying agent is carrageenan.
  • Carrageenan is preferred because of its solubility in water and its ability to protect the drug from damage during the freeze-drying step
  • Lambda, Iota, Kappa carrageenan may be used, although Lambda carrageenan is preferred.
  • the viscosity modifying agent and, in particular, the polysaccharide may form 0.8 to 10 weight % of the freeze- dried tablet.
  • the viscosity modifying agent and, in particular, the polysaccharide forms 1 to 6 weight %, more preferably 1.5 to 4 weight % of the freeze-dried tablet.
  • the total amount of viscosity modifying agent and, in particular, the polysaccharide in the freeze-dried tablet is preferably less than 6 weight %, more preferably less than 4 weight %.
  • the freeze-dried tablet comprises carrageenan in an amount of 1 to 6 weight %, preferably 1.5 to 4 weight %.
  • the total amount of carrageenan in the freeze- dried tablet is preferably less than 6 weight %, more
  • the binder and viscosity modifying agent are preferably separate or distinct components of the freeze-dried tablet of the present invention.
  • the binder and viscosity modifying agent it is preferable for the binder and viscosity modifying agent not to consist solely of a single component, such as Gum Arabic.
  • the relative concentrations of the binder and viscosity modifying agent can be controlled to provide the medium with the desired properties. This cannot be achieved if the binder and viscosity modifying agent consists solely of one component, such as Gum Arabic.
  • the weight ratio of the binder to the viscosity modifying agent may be 3-50:1, preferably 15-40:1, more preferably 20- 30:1. In one embodiment, the weight ratio of the
  • the freeze-dried tablet comprises gelatin and carrageenan in a weight ratio of 3-50:1,
  • cryoprotecting drug particles As a result, the particles remain intact and suspended in the medium during the freezing step, allowing the suspension to be lyophilized to form tablets that, advantageously, disintegrate quickly upon contact with saliva. This allows the drug particles to be released in the oral cavity and then easily swallowed and transported to the site of absorption.
  • the particles comprising one or more drugs may each comprise at least one drug and at least one excipient.
  • the excipient may mask the taste of the drug, modify the rate of release of the drug and/or protect the drug from possible degradation.
  • the particles each comprise a drug-containing core encapsulated and/or coated by one or more layers of polymer.
  • the polymer may control the rate of release of the drug, protect the drug from possible degradation and/or simply mask the taste of the drug.
  • the polymer layer (s) are intended to control the rate of release of the drug, the polymer layer (s) may be selected to provide immediate, extended, delayed or pulsed drug delivery, allowing the rate of release of the drug to be tailored as required.
  • the polymer layer (s) may be enteric coatings. Such coatings are stable under the highly acidic pH conditions of the stomach. However, under the less acidic conditions of the small intestine, the
  • coatings degrade rapidly, allowing the drug(s) to be released and absorbed in the small intestine.
  • the drug(s) is protected from the highly acidic conditions of the stomach and this reduces the risk of the drug being degraded before its reaches its site of absorption in the small intestine.
  • polymers that can be used to coat the drug(s) include cellulosic and/or acrylic polymers. Specific examples include Aquacoat ® , Surelease ® and/or Eudragit ® . The coating may be applied by known fluidized bed coating techniques, such as those described in US 4,623,588.
  • the particles comprising one or more drugs may take the form of pellets or pellet cores.
  • Each pellet/pellet core may comprise at least one drug, at least one excipient and at least one polymer.
  • the pellets/pellet cores may be prepared by any suitable technique including extrusion/spheronisation, dry or wet granulation, spray drying and freeze drying.
  • the drug particles incorporated into the tablet of the present invention may be any suitable size.
  • the particles are microparticles .
  • Such microparticles have diameters of 1 to 2000 microns, preferably 100 to 1000
  • microns more preferably 300 to 800 microns.
  • the particles may form 5 to 60 weight %, preferably 20 to 40 weight % of the freeze-dried tablet.
  • the weight ratio of the total weight of binder and viscosity modifying agent to the total weight of the particles comprising the one or more drugs is 0.3-4:1, more preferably 1-2:1.
  • the freeze-dried tablet of the present invention may include further excipients . These include fillers,
  • disintegrants thickening agents, stabilizers, surfactants, antioxidants, sweeteners, flavouring agents, preservative, taste-masking agents, absorption enhancers, pH modifying agents, bacteriostatic agents and colouring agents. Mixtures of two or more of these excipients may also be employed. These further excipients may form 0 to 10 weight %, preferably 2 to 6 weight % of the freeze-dried tablet.
  • the tablet additionally includes alanine and/or mannitol.
  • alanine and/or mannitol act as matrix-supporting or disintegration-enhancing agents, respectively. They may also act as crystallising agents to provide extra stability during and after freeze drying process.
  • Alanine in particular, is preferred, as it can help to improve the structural integrity (e.g. hardness) of the resulting tablet.
  • the freeze-dried tablet comprises weight %, preferably 20 to 50 weight % mannitol. In another embodiment, the freeze-dried tablet includes 10 to 60 weight % alanine, preferably 20 to 50 weight % alanine.
  • the freeze-dried tablet of the present invention may be used in a method of treatment of the human or animal body by therapy.
  • the freeze-dried tablet may be used in the treatment of constipation, depression, drug addiction, diabetes, diarrhoea, epilepsy, fungal infection, headache, heart burn, gout, GORD, hypertension, malaria, migraines, Parkinson's disease, cancer, viral infections, bacterial infections, eczema, local or systemic pain, elevated
  • Any suitable drug may be present in the particles of the freeze-dried tablet of the present invention.
  • the drug(s) may be selected from an analgesic or antiinflammatory agent, an anthelmintic, an anti-arrhythmic agent, an anti-coagulant, an anti-depressant, an anti-diabetic agent, an anti-epileptic agent, an anti-fungal agent, an anti-gout agent, an anti-hypertension agent, an anti-malarial, an antimigraine agent, an anti-muscarinic agent, an anti-neoplastic agent, an anti-protozoal agent, an anti-thyroid agent, an anxiolytic, a sedative, a hypnotic agent or a neuroleptic agent, a corticosteroid, a diuretic, an ant i-Parkinsonian agent, a gastro-intestinal agent, a histamine Hl-receptor antagonist, a lipid regulating agent, an anti-anginal agent, a thyroid agent, a nutritional agent, an antipyretic agent, an antibacterial agent, an immunosuppress
  • prostaglandin a vaccine, a cough suppressant, a local
  • anaesthetic an antisera, an opioid analgesic, a stimulant, a viral vector for gene therapy, an anti allergic agent, a cardio protective agent, an anti obesity agent, an oral contraceptive, an anti dementia, a fertility agent, a
  • cholinesterase inhibitor and an anti cholinergic agent or a therapeutic mixture thereof.
  • Analgesics and anti-inflammatory agents aloxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen,
  • Anthelmintics albendazole, bephenium hydroxynaphthoate , dichlorophen, ivermectin, mebendazole, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.
  • Anti-arrhythmic agents amiodarone HC1, disopyramide , quinidine sulphate.
  • Anti-bacterial agents benethamine penicillin, cinoxacin, ciprofloxacin HC1, clarithromycin, clofazimine, cloxacillin, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine , tetracycline, trimethoprim.
  • Anti-coagulants dicoumarol, dipyridamole, nicoumalone, phenindione.
  • Anti-constipation docusate sodium, sodium picosulphate, sennosides, tegaserod maleate.
  • Anti-depressants amoxapine, maprotiline HC1,
  • Anti-diabetics acetohexamide , chlorpropamide,
  • glibenclamide gliclazide, glipizide, tolazamide, insulin tolbutamide .
  • Anti-diarrhoea loperamide HCL, Bismuth subsalicylate.
  • Anti-epileptics beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide , methylphenobarbitone, phenacemide, phenobarbitone, phenytoin, phensuximide,
  • Anti-fungal agents amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,
  • griseofulvin itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HC1, terconazole, tioconazole, undecenoic acid.
  • Anti-gout agents allopurinol, probenecid, sulphin- pyrazone .
  • Anti-gastro-oesophageal reflux disease (GORD) rabeprazole sodium, esomeprazole magnesium, famotidine,
  • Anti-heart burn Omeprazole magnesium, famotidine,
  • Cimetidine Cimetidine, Ranitidine HC1.
  • Anti-headache Paracetamol/metoclopramide hydrochloride.
  • Anti-hypertensive agents amlodipine, diazoxide,
  • felodipine isradipine, minoxidil, nicardipine HC1
  • nifedipine nimodipine, prazosin HCl, reserpine, benazepril, Verapamil hydrochloride.
  • Anti-malarials amodiaquine, chloroquine, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulphate .
  • Anti-migraine agents dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen maleate.
  • Anti-muscarinic agents atropine, benzhexol HCl,
  • Anti-protazoal agents clioquinol
  • diiodohydroxyquinoline diloxanide furoate, dinitolmide, furzolidone, metronidazole, nitrofurazone , tinidazole.
  • Anti-thyroid agents carbimazole, propylthiouracil.
  • alprazolam amylobarbitone, barbitone, bromazepam
  • bromperidol brotizolam, butobarbitone, carbromal
  • chlordiazepoxide chlormethiazole
  • chlorpromazine clobazam
  • clozapine diazepam
  • droperidol ethinamate
  • fluanisone flunitrazepam
  • fluopromazine flupenthixol decanoate
  • fluphenazine decanoate flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine,
  • Cardiac Inotropic agents digitoxin, digoxin, lanatoside C, medigoxin.
  • Corticosteroids beclomethasone, betamethasone,
  • budesonide cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone,
  • fluticasone propionate hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.
  • Diuretics acetazolamide , amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.
  • Anti-parkinsonian agents bromocriptine mesylate.
  • Gastro-intestinal agents bisacodyl, cimetidine,
  • Lipid regulating agents bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol, atorvastatin calcium, ezetimibe, simvastatin.
  • Nitrates and other anti-anginal agents amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, pentaerythritol tetranitrate .
  • Nutritional agents betacarotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K.
  • Opioid analgesics codeine, dextropropyoxyphene,
  • Sex hormones clomiphene citrate, danazol, ethinyl estradiol, medroxyprogesterone acetate, mestranol,
  • the viral vector may be a retrovirus (such as Moloney murine leukaemia virus) , a lentivirus, an adenovirus, an adeno-associated virus (AAV) or a nanoengineered substance such as Ormosil.
  • retrovirus such as Moloney murine leukaemia virus
  • lentivirus such as Moloney murine leukaemia virus
  • AAV adeno-associated virus
  • nanoengineered substance such as Ormosil.
  • Anti allergic agent promethazine HC1, Chlorpheniramine maleate, diphenhydramine HC1, loratadine.
  • Cardio protective agent aspirin, dexrazoxane.
  • Anti obesity agent orlistat, sibutramine HC1,
  • methamphetamine HC1 methamphetamine HC1, phentermine HC1.
  • Oral contraceptive levonorgestrel , norgestrel, ethinyl estradiol, drospirenone .
  • Anti dementia donepezil HC1, rivastigmine tartrate, memantine HC1.
  • Cholinesterase inhibitor donepezil hydrochloride, galantamine hydrobromide .
  • Anti cholinergic agent Benzhexol, ipratropium bromide.
  • Vaccine typhoid Vaccine, OPV (oral polio vaccine).
  • derivatives thereof may be substituted for the drugs listed above. Mixtures of drugs may be used.
  • the drug is preferably present in the tablet in a pharmaceutically effective amount.
  • the tablet comprises from 0.0001% to 55% by weight of the drug based on the total weight of the tablet. More preferably, the tablet comprises from 5% to 50%, from 10% to 40%, or from 20% to 30% by weight of the drug based on the total weight of the tablet.
  • the particles comprising one or more drugs are first suspended in a medium comprising (i) the binder
  • a pharmaceutically acceptable solvent may be used to form the tablets. Suitable solvents include water, isopropanol, glycol and/or acetone.
  • the medium has a viscosity that allows the particles to be suspended for the duration of the freeze- drying process. While highly viscous suspending media can reduce the risk of settling or sedimentation, they can also lead to tablets that do not readily disintegrate in the oral cavity. With the present invention, however, the specific binder and viscosity modifying agents employed allow
  • the resulting tablets not only contain drug particles are homogenously dispersed, but also disintegrate readily, for example, when placed in the oral cavity .
  • the viscosity of the medium is desirably from 50 to 500 mPa.s, more preferably from 100 to 300 mPa . s .
  • the desired viscosity of the medium may vary, depending on the size of the drug particles and their densities. However, by varying the relative amounts of e.g. the binder, viscosity modifying agent and/or solvent, the viscosity of the medium may be tailored to meet a range of applications.
  • viscosity measurements may be made with a
  • Brookfield LVT viscometer with its spindle number 3 rotating at speed of 20 rpm at room temperature in a 100 mL beaker with the spindle guard.
  • the amount of solvent in the medium may be 60 to 95 weight %, preferably 70 to 90 weight %, more preferably 80 to 90 weight %.
  • proteinaceous material in the medium may be 10 to 60 weight %, preferably 20 to 45 weight %, more preferably 30 to 40 weight %.
  • the preferred binder is
  • the viscosity modifying agent and, in particular, the polysaccharide may form 0.8 to 10 weight % of the medium.
  • the viscosity modifying agent and, in particular, the polysaccharide forms 1 to 6 weight %, more preferably 1.5 to 4 weight % of the medium.
  • the total amount of viscosity modifying agent and, in particular, the polysaccharide in the medium is preferably less than 6 weight %, more preferably less than 4 weight %.
  • the preferred viscosity modifying agent is carrageenan.
  • the weight ratio of solvent to binder to viscosity modifying agent may be (1500 - 2200) : (20 - 80) : (2 - 2), preferably (1800 - 2000) : (30 - 50) : (2 - 2) .
  • the amount of drug added to the medium may be varied as required to provide the desired concentration in the tablet.
  • the suspension is frozen and, preferably, maintained at a low temperature then annealed for a period of time.
  • the frozen solution or suspension is annealed at a temperature of from -70°C to -5°C for at least 5 hours. More preferably, the frozen solution or suspension is annealed at a temperature of from -40°C to -10°C for at least 5 hours.
  • the frozen solution or suspension is annealed at a temperature of from -30°C to -10°C for at least 10 hours. Annealing the frozen solution or suspension leads to the formation of an improved product .
  • a crystallising excipient may be added to the solution or suspension.
  • Adding the crystallising excipient to the solution or suspension modifies the thermal profile of the frozen material.
  • the modified thermal profile allows freeze-drying at higher temperatures and consequently decreases the primary drying time.
  • the resulting tablet may also have better structural integrity, reducing the risk of it disintegrating or crumbling prior to being administered.
  • the crystallising excipient may be selected from alanine and mannitol. Alternatively or
  • the crystallising excipient may form 10 to 60 weight %, preferably 20 to 50 weight % of the final tablet .
  • Figure 1 is a graph showing how the viscosity of a suspending medium varies with gelatin and carrageenan
  • Solutions were prepared by dissolving gelatin in 100 ml of double distilled water at about 40 degrees C to obtain gelatin concentrations of 3, 4 and 5% (w/v) , respectively. Carrageenan was then added to each of the solutions at
  • Solutions were prepared by dissolving gelatin in 100 ml of double distilled water at about 40 degrees C to obtain gelatin concentrations of 3, 4 and 5% (w/v) , respectively. Carrageenan was then added to each of the solutions at
  • compositions of the solutions are shown in Table 1.
  • the hardness properties of the tablets were investigated with a texture analyser (QTS 25 Brookfield, Essex, UK) equipped with a 25 kg load cell.
  • the instrument was
  • Example 2 was repeated with compositions comprising gelatin and 30% alanine (w/w of the dried materials) .
  • Gelatin 0.5g
  • carrageenan 0.02g
  • alanine 0.3g
  • suspending medium having a viscosity of 172 ⁇ 21.3 mPas.
  • the medium was used to suspend enteric coated omeprazole pellets having the following characteristics:
  • the drug recovery of the pellets was determined by placing the pellets in a gastric solution for 1 hour. 91.24% of the pellets were recovered, showing that the enteric coating remained substantially intact under the low pH conditions of the gastric solution.
  • the resulting suspension was poured into a mould, frozen at -80 degrees C for about 60 minutes and freeze-dried
  • the resulting tablet had a disintegration time of 14 seconds and a hardness of 17.2 ⁇ 21.3N.
  • the latter was investigated with a texture analyser (QTS 25 Brookfield, Essex, UK) as described in Example 2 above.
  • the drug recovery of the tablet was determined by placing the tablet in a gastric solution for 1 hour. 93.14 ⁇ 1.22 % of the pellets were recovered, showing that there was no damage to the pellets during tablet manufacture.

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Abstract

L'invention concerne un comprimé lyophilisé comprenant des particules comprenant un ou plusieurs médicaments, un liant comprenant un matériau protéique et un agent modifiant la viscosité comprenant un polysaccharide.
PCT/GB2011/000502 2010-04-09 2011-03-31 Comprimé lyophilisé Ceased WO2011124876A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1005976.4A GB201005976D0 (en) 2010-04-09 2010-04-09 A freeze-dried tablet
GB1005976.4 2010-04-09

Publications (2)

Publication Number Publication Date
WO2011124876A2 true WO2011124876A2 (fr) 2011-10-13
WO2011124876A3 WO2011124876A3 (fr) 2012-05-10

Family

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Family Applications (1)

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PCT/GB2011/000502 Ceased WO2011124876A2 (fr) 2010-04-09 2011-03-31 Comprimé lyophilisé

Country Status (2)

Country Link
GB (1) GB201005976D0 (fr)
WO (1) WO2011124876A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190083391A1 (en) * 2017-09-18 2019-03-21 Balto Therapeutics Orally disintegrating tablets for treatment of peptic ulcer
WO2020109485A1 (fr) * 2018-11-29 2020-06-04 Catalent U.K. Swindon Zydis Limited Vaccin orodispersible comprenant des virosomes
US11737987B2 (en) 2019-12-17 2023-08-29 9286-3620 Quebec Inc. Oral delivery systems based on in situ forming protein/polysaccharide coacervates
RU2808276C2 (ru) * 2018-11-29 2023-11-28 Каталент Ю.Кей. Суиндон Зайдис Лимитед Перорально диспергируемая вакцина, содержащая виросомы

Citations (1)

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Publication number Priority date Publication date Assignee Title
US4623588A (en) 1984-02-06 1986-11-18 Biotek, Inc. Controlled release composite core coated microparticles

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EP0617613B1 (fr) * 1991-12-20 1996-05-29 Pfizer Inc. Elements d'administration de medicament profiles et poreux, et procedes de production
CA2128821A1 (fr) * 1993-07-27 1995-01-28 Dilip J. Gole Forme pharmaceutique lyophilisee et methode de separation

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US4623588A (en) 1984-02-06 1986-11-18 Biotek, Inc. Controlled release composite core coated microparticles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DISINTEGRATION, pages 2670 - 2672
GUIDANCE FOR INDUSTRY: ORALLY DISINTEGRATING TABLETS, December 2008 (2008-12-01)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190083391A1 (en) * 2017-09-18 2019-03-21 Balto Therapeutics Orally disintegrating tablets for treatment of peptic ulcer
WO2020109485A1 (fr) * 2018-11-29 2020-06-04 Catalent U.K. Swindon Zydis Limited Vaccin orodispersible comprenant des virosomes
CN113301917A (zh) * 2018-11-29 2021-08-24 康特伦英国斯温顿捷迪斯有限公司 包含病毒体的可经口分散疫苗
EP3886896A1 (fr) * 2018-11-29 2021-10-06 Catalent U.K. Swindon Zydis Limited Vaccin orodispersible comprenant des virosomes
US11224571B2 (en) 2018-11-29 2022-01-18 Catalent U.K. Swindon Zydis Limited Oral dispersible vaccine comprising virosomes
JP2022510372A (ja) * 2018-11-29 2022-01-26 キャタレント・ユーケー・スウィンドン・ザイディス・リミテッド ビロソームを含む経口分散性ワクチン
US11523988B2 (en) 2018-11-29 2022-12-13 Catalent U.K. Swindon Zydis Limited Oral dispersible vaccine comprising virosomes
RU2808276C2 (ru) * 2018-11-29 2023-11-28 Каталент Ю.Кей. Суиндон Зайдис Лимитед Перорально диспергируемая вакцина, содержащая виросомы
JP2024029053A (ja) * 2018-11-29 2024-03-05 キャタレント・ユーケー・スウィンドン・ザイディス・リミテッド ビロソームを含む経口分散性ワクチン
IL282371B1 (en) * 2018-11-29 2024-11-01 Catalent Uk Swindon Zydis Ltd Oral dispersible vaccine comprising virosomes
IL282371B2 (en) * 2018-11-29 2025-03-01 Catalent Uk Swindon Zydis Ltd Orodispersible vaccine containing virosomes
US11737987B2 (en) 2019-12-17 2023-08-29 9286-3620 Quebec Inc. Oral delivery systems based on in situ forming protein/polysaccharide coacervates

Also Published As

Publication number Publication date
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WO2011124876A3 (fr) 2012-05-10

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