MXPA01007569A - Fast dispersing dosage forms free of gelatin - Google Patents
Fast dispersing dosage forms free of gelatinInfo
- Publication number
- MXPA01007569A MXPA01007569A MXPA/A/2001/007569A MXPA01007569A MXPA01007569A MX PA01007569 A MXPA01007569 A MX PA01007569A MX PA01007569 A MXPA01007569 A MX PA01007569A MX PA01007569 A MXPA01007569 A MX PA01007569A
- Authority
- MX
- Mexico
- Prior art keywords
- solid dosage
- dosage form
- starch
- active ingredient
- dosage forms
- Prior art date
Links
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Abstract
The present invention relates to fast dispersing solid dosage forms that preferably dissolve in the oral cavity within sixty (60), more preferably within thirty (30), most preferably within ten (10) seconds. A novel feature of the solid dosage forms according to the invention reside in the fact that the composition is essentially free or absolutely free of mammalian gelatin. It has been discovered that the use of certain modified starches at concentrations from 20 to 90%by weight of the solid dosage form prepares dosage forms that are mechanically and chemically stable and are able to deliver higher concentrations of an active ingredient than the heretofore utilized gelatin based fast dispersing solid dosage forms. Further, the solid dosage forms according to the invention are obtainable by removing a solvent, such as water, from a mixture comprising an active ingredient, a modified starch and a matrix forming agent via freeze drying.
Description
FAST DISPERSION DOSAGE FORMS GELATIN FREE
Technical Field of the Invention
This invention relates to a pharmaceutical composition for oral administration in the form of a rapid dispersion dosage form. The novel dosage form is essentially free of mammalian gelatin and comprises at least one matrix forming agent and a modified lactose starch.
Background of the Invention
The most common pharmaceutical dosage form is the tablet The main limitations of the tablets include poor compliance on the part of the patient due to the difficulty of swallowing the tablets and a lack of bioavailability of the active ingredient by ineffective dissolution of the tablet . Therefore, there is a need in the medical community for rapidly soluble dosage forms. A variety of methods have been used to overcome the drawbacks of tablets, including effervescent tablets, chewable tablets, disintegrating agents and wicking agents. More recently, rapid dispersion dosage forms, which are designed to release the active ingredient in the oral cavity, have been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to administer a wide range of drugs. Dosage forms that disperse more rapidly utilize gelatin as a vehicle or structure-forming agent. Typically, gelatin is used to give sufficient strength or coherence to the dosage form to prevent rupture during packing removal, but once placed in the mouth the gelatin allows immediate dissolution of the dosage form .
The gelatin B. P. that is normally used in these formulations, is defined as a protein that is obtained. by partial hydrolysis of the collagenous tissues of an animal, such as the skin, tendons, ligaments and bones. However, this gelatin derived from mammals has a soft flavor and, therefore, needs the use of sweeteners and flavors in these fast dispersing dosage forms to mask the flavor of the active ingredient. When conventional gelatin derived from a mammal is used in the production of these fast dispersing dosage forms, it is necessary to heat the gelatin solution in order to effect a solution. This heating step increases the processing time and incurs the heating costs and, therefore, increases the overall cost of the process. Conventional processing may require maintenance times of up to 48 hours. It has been observed that during this period of time the viscosity of the gelatin-based mixture can be increased, which leads to processing difficulties. Furthermore, the use of mammalian gelatin produces dosage forms that rapidly absorb water and this can lead to a contraction of the dosage form during normal storage periods. Another problem that is known and associated with the forms of Rapid dissolving dosing based on gelatin is the lack of homogeneity and sedimentation of the liquid mixture during maintenance periods, as some mixtures incorporate the substance, active as suspended particles. The use of mammalian derived gelatin results in a settling of the active ingredient due to the low viscosity of the gelatin of the mammalia. A benefit of the present invention is that the modified starches described herein substantially overlap the homogeneity and settling problems associated with mammalian gelatin. Another benefit associated with the use of modified starches in the preparation of rapidly dissolving dosage forms resides in the discovery that the modified starch dosage form is capable of higher drug loads. These are beneficial in that for a given dose of the active ingredient, the dosage form of modified starch may be substantially less than the conventional gelatin dosage form. Other materials have been tried instead of gelatin in fast dispersion dosage form, but although they can form strong products (reduced propensity to fracture and rupture) they generally disperse slowly or form a gummy mass in the mouth. It has now been discovered that the modified starches can be used in place of the mammalian-derived gelatin to prepare fast dispersing dosage forms. According to the present invention, therefore, there is provided a pharmaceutical composition for oral administration in a rapid dispersion dosage form designed to rapidly release an active ingredient in the oral cavity, characterized in that the essentially gelatin-free composition comprises starch. modified and at least one matrix forming agent.
The invention provides the possibility of reducing or preferably eliminating gelatin from fast dispersing dosage forms (FDDF). The modified starches can be used as the main structure forming agent in the FDDF to form physically resistant products while retaining the desired characteristics of a rapid dispersion of the products. By suitable selection of the modified starch, it is possible to obtain particularly desirable properties of solubility in cold water, without changes in solution viscosity over time, and improved stability and physical strength of the dosage form. The use of the modified starch allows the level of the sweetening / flavoring agents that have previously been used to improve the taste of the dosage form to be reduced or eliminated. The use of a material from a botanical source as opposed to the use of an animal source material also has the benefit of eliminating the exposure of agents such as BSE. Starch can be considered as a condensation of the glucose polymer. These constituents of glucose are present in the form of anhydroglucose units (AGU). If the starch is subjected to treatment, either with acids or certain enzymes, it can be completely degraded, by hydrolysis of the glycosidic bonds, in its constituent units of glucose. Most starches consist of two types of glucose polymers, each having a wide range of molecular sizes: (i) a straight-chain molecule called amylose, which can contain up to 6,000 glucose units bound by 1 to 4 bonds and, (ii) a highly branched polymer called amylopectin, which consists of short chains (10 to
60 glucose units) connected by μ -1.6-links. The glucose units of the starch molecules contain a hydroxyl main group at carbon-6 and a secondary hydroxyl group at carbon-2 and carbon-3. The starch molecules have a multitude of hydroxyl groups, which confer hydrophilic properties on the starch and lead to the dispersibility of the starch when heated with water. However, these hydroxyl groups also tend to attract each other, and form hydrogen bonds between the adjacent starch molecules and prevent dissolution in cold water. Natural starch can be altered by a physical, chemical or enzymatic treatment to alter its properties or confer new ones. The properties of these modified starches "include solid viscosity ratios, gelatinization and cooking characteristics, resistance to viscosity disintegration due to acids, resistance to heat cutting and / or mechanical forces, an ionic character and a hydrophilic character.
A wide range of modified starches are commercially available and are useful in the present invention and include: Pre-gelatinized starches, which are produced by drum drying or extrusion; Low viscosity starches, which are produced by controlled hydrolysis of glycosidic bonds; Dextrins, which are produced by drying by roasting the starch in the presence of a small amount of acid;
Acid-modified starches, which are produced by suspending in dilute acid until the required viscosity is reached; Oxidized starches, in which oxidizing agents cause the introduction of carbonyl or carboxyl groups, where depolymerization occurs, which leads to a retrogradation and diminished gelation capacities; Enzymatically modified starch, which is produced by controlled enzymatic degradation to achieve the physicochemical properties required; Crosslinked starches, wherein the di- or polyfunctional reactants react with the hydroxyl groups to form crosslinked bonds, examples of the specific reagents include phosphorus oxychloride, sodium trimetaphosphate and epichlorohydrin; and Stabilized starches, the starches are reacted with etherifying or esterifying reagents in the presence of an alkaline catalyst to give a wide range of products.
Background of the Invention The patent of E.U.A. No. 5,120,549 discloses a fast dispersing dosage form which is first prepared by solidifying a dispersed matrix forming system in a first solvent and subsequently contacting the solidified matrix with a second solvent which is substantially miscible with the first solvent at a temperature lower than the solidification temperature of the first solvent, the matrix-forming elements and the active ingredient are substantially insoluble in the second solvent, while the first solvent is substantially removed resulting in a fast dispersing dosage form. The patent of E.U.A. No. 5,079,018 discloses a fast dispersing dosage form comprising a main or porous structure of a water soluble hydratable gel or of a foam forming material that has been hydrated with water, which has become rigid in the hydrated state with an agent stiffener and dehydrated with a liquid organic solvent at a temperature of about 0 ° C or less to leave spaces in place of the hydration liquid. The International Application Published number WO
93/12769 (PCT / JP93 / Ó1631) describes the very low density rapid dispersion dosage forms which are formed by gelation, with agar, aqueous systems containing the matrix forming elements and the active ingredient, and then removing the water by forced air or vacuum drying. The patent of E.U.A. No. 5,298,261 discloses rapid dispersion dosage forms comprising a partially collapsed matrix network that has been vacuum dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dehydrated below the equilibrium freezing point of the matrix. In the International Application published number WO
91/04757 (PCT / US90 / 05206) discloses rapid dispersion dosage forms containing an effervescent disintegration agent, designed to effervesce in contact with saliva to produce a rapid disintegration of the dosage form and a dispersion of the active ingredient in the oral cavity The patent of E.U.A. No. 5,595,761 discloses a particulate support matrix for use in the manufacture of a fast dissolving tablet, comprising; a first polypeptide component having a net charge when in solution, for example, a non-hydrolyzed gelatin; a second polypeptide component having a net charge of the same sign as the net charge of the first polypeptide component when in solution, for example, hydrolysed gelatin; and an ingredient for loading, and wherein the first polypeptide component and the second polypeptide component together comprise about 21 to 20% by weight of the particulate support matrix and wherein the ingredient for loading comprises approximately 602 to 962 by weight of the particulate matrix; and wherein the second polypeptide component has a solubility in a larger aqueous solution than the first polypeptide component and wherein the mass (mass ratio of the first polypeptide component for the second polypeptide component) is from about 2: 1 to approximately 1:14; and wherein when the support matrix is introduced in an aqueous environment, the support matrix disintegrates within less than about 20 seconds. EP-B-0690747 discloses particles comprising an excipient forming a matrix and at least one active ingredient evenly distributed in the mass of the matrix which is prepared by a process comprising the steps of preparing a homogeneous slurry. with a viscosity below 1
Pa.s, which is quantified at room temperature (15-20 ° C), of at least one active ingredient, a physiologically acceptable hydrophilic excipient and water; Extrude the resulting homogenous mixture and cut the extruded product to give wetted particles; freezing the resulting particles as they fall by gravity through a flow of inert gas at a temperature below 0 ° C; and drying the particles by lyophilization. Australian Patent No. 666666 discloses a multiparticulate tablet having a mixture of excipients in which the active substance is present in the form of coated microcrystals or optionally coated microgranules. These tablets disintegrate in the mouth in an extremely short period of time, typically in less than 60 seconds. The patent of E.U.A. No. 5,382,437 discloses a vehicle of porous material having sufficient rigidity to carry and administer an active ingredient which is capable of rapid dissolution by saliva and which is formed by freezing a liquefied solution of ammonia comprising liquid ammonia, a gel or material of liquid ammonia-soluble foam and a stiffening agent for the gel or foam material selected from a group consisting of a monosaccharide, a polysaccharide and combinations thereof, and removing the ammonia from the frozen material that is formed in this way by causing a transfer of the ammonia material from the frozen state to the gaseous state and, therefore, leaving spaces in the carrier material instead of the frozen ammonia.
Published International Application No. WO 93/13758 (PCT / US92 / 07497) discloses tablets of increased physical strength which are prepared by combining and compressing a workable binder, excipients and a pharmaceutically active agent in a tablet, melting the binder in the tablet and then solidify the binding agent. In one embodiment, a disintegrating agent is used to increase the disintegration rate of the tablet after oral intake. In another embodiment, a volatile component is used to form porous tablets. In some modalities, it disintegrates in the mouth in less than 10 seconds. The patents of E.U.A. Nos. 3,885,026 and 4,134,943 also describe porous fast-dispersion tablets and a method of increasing their physical strength first by compressing the tablet and then volatilizing an easily volatile solid adjuvant that is incorporated into the tablet to achieve the desired porosity. International Published Application WO 94/14422 describes a process for freeze drying the discrete units in which the solvent is removed under conditions in which the solvent is evaporated from the solid through the liquid phase to a gas, instead of Sublimate from a solid to a gas as in lyophilization. This is achieved by vacuum drying at a temperature below the equilibrium freezing point of the composition so that at this point the solvent (such as water) changes phase. EP-0693281 to Lilly S.A. it relates to pharmaceutical formulations of fluoxetine or acid addition salts thereof which are placed on tablets dispersible by direct compression. This reference does describe the use of sodium starch glycolate as a disintegrating agent. Sodium starch glycolate is used in this reference at concentrations exceeding 52 by weight, preferably at concentrations between 9.52 and 172. This reference does not disclose a solid fast dispersing dosage form containing at least 202 by weight per cent. at least one modified starch and a process for modifying the dosage form wherein a solvent is removed from a mixture comprising an active ingredient, a modified starch and a matrix forming agent. EP-0599767 relates to a process for the preparation of dispersible Diclofenac tablets. The process is characterized by the compression of a mixture consisting of granules containing a hydrophilic lubricant and a disintegrating agent, the active ingredient and other excipients. The excipients include microcrystalline cellulose, corn starch and lactose. The examples also indicate the use of carboxymethyl starch. This reference fails to suggest -or describe a solid fast dispersing dosage form containing at least one active ingredient, at least one modified starch at a concentration ranging from 202 to 902, by weight of the solid dosage and, for at least, a matrix-forming agent. In addition, this reference does not show the current process of the invention to form a solid dosage form wherein the solvent is removed from the mixture by freeze-drying.
EP-0159631 to National Starch & Chemical Corporation relates to compressible starches as binders for tablets or capsules. This reference describes a variety of chemically modified starches which are suitable for use as binders in tabletting operations, especially by direct compression and which are also useful as binders, diluents and the like for filling operations capsules These suggestions do not disclose or suggest the use of these modified starches in fast dispersing solid dosage forms that can be obtained by removing a solvent from a mixture comprising an active ingredient., a modified starch and a matrix forming agent. GB-2172006 relates to excipients to be used in the compression molding of the tablets. This reference discloses excipients which are prepared by dispersing a cellulose powder and a hydroxypropyl starch powder in an aqueous solution and thereafter spray-drying the dispersion. This preparation is described as being useful in the compression molding of the tablets. There is no suggestion or description of a solid fast dispersing dosage form containing at least one modified starch in concentrations ranging from 20"to 902 by weight of the dosage form wherein the dosage form can be obtained by removing a solvent of a mixture comprising an active ingredient, a modified starch and a matrix forming agent US Patent Number 5,629,003 to Horstmann et al. relates to fast disintegrating preparations similar to sheets comprising from 20"to 602" of at least one film-forming agent, ie, mannitol, 2"to 402 by weight of at least one gel-forming agent, ie, modified starch, an active substance and up to 40- by weight of At least one inert filling agent, the product of this reference is spread on siliconized paper and dried at 80 ° C for 15 minutes.This reference does not suggest or describe a solid form The rapid dispersion dosage containing at least one modified starch at concentrations ranging from 202 to 902 by weight of the solid dosage form is obtained by removing a solvent from a mixture comprising an active ingredient, a modified starch and an agent matrix former. An article by Chemical Abstracts, entitled 'Preparation of Emulsifying Agents for Pharmaceuticals, Cosmetics and Foods', Vol. 110, No. 10, Summary No. 82495 describes the use of modified starches and an emulsifying agent in the pharmaceutical industry. suggests or describes a solid fast dispersing dosage form comprising at least one modified starch at a concentration ranging from 202 to 902 by weight, wherein the dosage form is obtained by removing a solvent from a mixture comprising an ingredient active, the modified starch and a matrix forming agent.
Brief Description of the Invention A solid dispersive dosage form designed to rapidly release an active ingredient in the oral cavity is characterized in that the dosage form is essentially free of mammalian gelatin and comprises: less an active ingredient; at least one modified starch at a concentration ranging from 202 to 902 by weight of a solid dosage form; and at least one matrix forming agent; wherein the solid dosage form is obtained by removing a solvent from a mixture comprising the active ingredient, the modified starch and the matrix forming agent. In one embodiment of the invention, the solid dosage form comprises at least one modified starch selected from a group consisting of starches having their esterified hydroxyl groups, hydroxypropyl phosphated di-starch, an enzymatically modified starch, a -pregelatinized starch phosphate, hydroxyethyl starch, an acetylated and pregelatinized phosphatized di-starch, and a pregelatinized and purified starch.
In a preferred embodiment, the solid dosage form according to the invention comprises from 502 to 902 by weight of the modified starch. While several specific examples are provided on the useful modified starches, a general characteristic of the modified starches useful in the fast dispersing solid dosage form according to the invention is that they are readily soluble or dispersible in water at room temperature. Another benefit associated with the modified starches used in the present invention is that the mixture of the active modified starch and the matrix forming agent exhibit a fairly consistent viscosity over a period of about 24 hours. The preferred solvent according to the invention is water.
The preferred matrix forming agent is mannitol.
The solid fast dispersing dosage forms according to the invention may also contain coloring agents, flavoring agents, excipients, multiple therapeutic agents and the like. In a preferred embodiment according to the invention, removal of the solvent from the mixture is preferably carried out by freeze-drying.
Detailed Description of the Invention As used herein and in the claims, the term "fast dispersing dosage form (FDDF)" refers to compositions that disintegrate / disperse within a period of 1 to 60 seconds, preferably from 1 to 30 seconds, more preferably 1 to 10 seconds, and particularly 2 to 8 seconds, after being placed in the oral cavity The dosage form of the present invention is similar to the dosage forms described in the United Kingdom patent. No. 1548022, that is, a solid dosage form of rapid dispersion comprising a network of the active ingredient and a water-soluble or water-dispersible carrier, which is inert towards the active ingredient, the network is obtained by sublimating the solvent from a composition in the solid state, this composition comprises the active ingredient and a solution of the carrier in a solvent.The point of distinction is that the starch mod ificado is used as a carrier instead of the conventional gelatin of a mammal. The fast dispersing dosage form according to the invention may also contain, in addition to the active ingredient and the modified starch, other matrix forming agents and secondary components. Suitable matrix forming agents for use in the present invention include materials derived from animal or vegetable proteins, such as non-mammalian gelatins, dextrins and soybean, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synic polymers such as polyvinyl pyrrolidone; and polypeptide / protein complexes or polysaccharides such as gelatin-acacia complexes. Matrix forming agents suitable for use in present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. One or more matrix forming agents can be incorporated into solution or suspension before solidification. matrix forming agent may be present in addition to a surfactant agent or excluding surfactant agent. In addition to forming matrix, matrix forming agent can assist in maintaining dispersion of any active ingredient within solution, suspension or mixture. This is especially useful in case active ingredients are not sufficiently soluble in water and should efore be suspended ra than "dissolved." Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, Coloring agents, flavoring agents, pH modifiers, sweetening agents or taste masking agents can also be incorporated into composition.suitable coloring agents include iron oxides of red, yellow, black and yellow and dyes FD &C, such as blue FD &C No. 2 and red FD &C No. 40. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavors and combinations of e, suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Suitable sweetening agents include aspartame, acesulfa e K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated active ingredients. In general, modified starch comprises from 5"to 99.52 by weight of FDDF solids, usually 202 to 902, usually 50 to 90 .. Any drug can be used as an active ingredient in composition of present invention. Suitable include, but are not limited to, those listed below:
Analgesics and anti-inflammatory agents: aloxiprine, auranofin, azapropazone, benorilate, diflunisal, etodolac, fenbufen, calcium fenoprofen, flurbiprofen, ibuprofen, indomethacin, etoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac . Anhelhelmintics: albendazole, befenium hydroxynaphthoate, cambendazole, dichlorophene, ivermectin, mebendazole, oxamniquine, oxfendazole, oxalole embonate, praziquantel, pyrantel embonate, thiabendazole. Anti-arrhythmic agents: amiodarone HCl, disopyramide, flecainide acetate, quinidine sulfate. Antibacterial agents: penicillin benetamine, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, etiona ida, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfaceta ida, sulfadiazine, sulfafurazole, sulfametotaxol, sulfapyridine, tetracycline, trimethoprim.
Anticoagulants: dicoumarol, dipyridamole, nicoumalone, fenindione. Antidepressants: amoxapine, cyclazindol, maprotiline HCl, mianserin HCl, nortriptyline HCl, trazodone HCl, trimipramine maleate. An idiabetic: acetohexamida, chlorpropamida, glibenclamida, gliclazida, glipizida, tolazamida, tolbutamida. Antiepileptics: beclamide, carbamazepine, clonazepam, etotoin, methoin, methsuximide, methylphenobarbitone, oxcarbazepine, parametadione, phenacemide, phenobarbitone, phenytoin, fensuximide, primidone, sultiame, and valproic acid. Antifungal agents: amphotericin, butononazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, terconazole, thioconazole, undecanoic acid. Anti-gout agents: allopurinol, probenecid, sulfinpyrazone.
Antihypertensive agents: amlodipine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, indoramin, isradipine, minoxidil,
Nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine, terazosin HCl. Anti-malaria agents: amodiaquine, chloroquine, chlorproguanil HCl, -halophantrine HCl, mefloquine HCl, proguanyl HCl, pyrimethamine, quinine sulfate. Anti-migraine agents: dihydroergotamine mesylate, ergota ina tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate. Anti-muscarinic agents: atropine, benzohexol HCl, biperiden, etqpropazine HCl, butyl hyosine bromide, hyosiamine, mepenzolate bromide, orphenadrine, oxyphenylcyamin HCl, tropicamide. Antineoplastic agents and Immunosuppressants: aminoglutethimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine "HCl, tamoxifen citrate, testolactone.
Anti-protozoal agents: benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole. Anti-thyroid agents: carbimazole, propylthiouracil. Anxiolytics, sedatives, hypnotics and neuroleptics: alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine, clobaza, clotiazepam, clozapine, diasepam, droperidol, etinamate, flunanizone, flunitrazepam, fluoprotnazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobanate, metaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, triazolam, zopiclone. β-blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol. Cardiac Inotropic Agents: amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin.
Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, deoximetasone, 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. Enzymes: Insonic anti-pair agents: bromocriptine mesylate, maleate of 'lisuride. Gastrointestinal agents: bisacodyl, cimetidine, cysapride, diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, wavenestrone HCl, ranitidine HCl, sulfasalazine. Histamine H receptor antagonists: acrivastine, astemizole, cinnarizine, cyclizine, cycloheptadine HCl, dimenhydrin, flunarizine HCl, loratadine, meclozine HCl, oxatomide, terfenadine, triprolidine. Lipid regulating agents: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.
Local anesthetics: Neuro-muscular agents: pyridostigmine. Nitrates and other anti-anginic agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate. Nutritional agents: beta-carotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K. Opioid analgesics: codeine, dextropropioxifen, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine. Oral vaccines: Vaccines are designed to prevent or reduce the symptoms of diseases of which the following are representative, but not an exclusive list: Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes , Typhoid, HIV, AIDS, Mumps, Scurvy, Diarrhea, Traveler, Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies, Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaire's Disease, Toxoplasmosis, Fever-Q , Hemorrhagic Fever, Hemorrhagic Fever of Argentina, Caries,
Chagas Disease, Urinary Tract Infection caused by E. coli, Pneumococcal Disease,
Mumps and Chikungunya. Vaccines to prevent or reduce the symptoms of other disease syndromes of which the following is representative, but not an exclusive list of causative organisms: Vibrio species, Salmonella species, Bordetella species, Haemophillus species,
Toxoplasmosis gondii, Cytomegalovirus, Species of
Chlamydia, Streptococcal species, Virus
Norwalk, Escherischia coli, Helicobateria pylori,
Rotavirus Neisseria gonorrhae, Neisseria meningititis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex, Clostridia Species, Sinsitium Virus
Respiratory, Klebsielia Species, Species of
Shigella, Pseudomonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species,
Varicella zoster, Species of Yersinia, Ross virus
River, J.C. Virus, Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica. Vaccines directed to non-infectious and immunoregulated disease conditions, such as topical and systemic allergic conditions such as Hay Fever, Asthma, Rheumatoid Arthritis and Carcinomas. Vaccines for veterinary use include those that are directed against Coccidiosis, Ne castle disease, Enzootic pneumonia, Feline leukemia, Atrophic rhinitis, Erysipelas, Foot-and-mouth disease, Pneumonia of pigs and other disease conditions and other infections and conditions of autoimmune diseases. that affect farm and companion animals.
Proteins, peptides and recombinant drugs: insulin (hexamic / dimeric / monomeric forms), glucagon, growth hormone (somatotropin), polypeptides or their derivatives, (preferably with a molecular weight from 100 to 300,000), calcitonins and synthetic modifications thereof , enkephalins, interferons (especially Alpha-2 interferon for the treatment of common colds), LHRH and analogs (nafarelin, buserelin, zolidex), GHRH
(Hormone releasing growth hormone), secretin, bradykinin antagonists, GRF
(vibrating factor of growth), THF, TRH (thyrotropin releasing hormone), analogs of ACTH, IGF
(insulin-like growth factors), CGRP
(peptide related to the calcitonin gene), atrial natriuretic peptide, vasopressin and the like
(DDAVP, lipresin), factor VIII, G-CSF (granulocyte colony stimulating factor), EPO
(erythropoitin)
Sex hormones: clomiphene citrate, danazol, ethinyloestradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, oestradiol, conjugated oestrogens, progesterone, stanazolol, stiboestrol, testosterone, tibolone.
Spermicides: nonoxynol 9 Stimulants: amphetamines, dexamfetamine, dexfenfluramine, fenfluramine, mazindol, pemoline. The precise amount of active ingredient depends on the selected drug. However, the active ingredient is generally present in an amount ranging from 0.2 to 95 percent, usually from 1 to 20 percent, by weight of the composition of the dry dosage form. The invention is further illustrated by the following Examples which are intended to be illustrative and not limiting. In the following, the FDDF Examples are prepared and analyzed in the absence of an active ingredient.
EXAMPLE 1 The following formulation is prepared:
Amilogum CLS is a starch whose hydroxyl groups have been esterified. It is commercially available from Avebe U.K., Ltd. of
South Hubersida, England. Mannitol is supplied by Roquette Ltd. of Kent, England. The starch is added to the purified water and heated to 60 ° C with stirring. The resulting mixture is maintained at 60 ° C for 10 minutes to effect the solution and subsequently cooled to room temperature. After the mixture has cooled sufficiently, add the mannitol and stir until it is completely dissolved. The mixture is dosed in PVC / PVdC vials with filling weights of 500 milligrams. The units are frozen in a flow of icy nitrogen gas and then dehydrated by freezing by suddenly increasing the temperature from -10 ° C to + 20 ° C at a pressure of 0.5 mbar.
EXAMPLE 2 The following formulation is prepared by adopting the procedure of Example 1.
Perfectagel MPT is a phosphonated dialmidon of hydroxypropyl and is commercially available from Avebe U.K., Ltd.
EXAMPLE 3 The following formulation is prepared:
Paselli MD10 is an enzymatically modified starch and is commercially available from Avebe U.K. Ltd.
The water is stirred with an electronic hand mixer and the starch and mannitol are added while stirring. No heat is required for this starch.
The solution is left stirring for 1.5 hours to equilibrate. The dispersion of the dosage forms in the mouth is smooth, fast and has a sweet taste.
EXAMPLE 4 The following formulation is prepared by adapting the procedure of Example 3
Avebe MD20 is an enzymatically modified starch which is commercially available from Avebe U.K., Ltd. The dosage forms that are prepared in Examples I to 4 give all rapid disintegration times in the mouth of less than 10 seconds.
EXAMPLE 5 Investigation in the Viscosity Profiles of a Variety of Modified Starches Formulations having the following composition were prepared.
The modified starches that are used are: Paselli Easygel, which is a pre-gelatinized phosphate starch. Paselli BC which is a pre-gelatinized acetylated phosphatized di-starch. Paselli WA4 which is a pre-gelatinized purified starch. All these modified starches are commercially available from Avebe, U.K., Ltd.
The powders are mixed dry and added to the vortex of the purified water. The mixtures are subsequently heated to 50 ° C and then homogenized with a S'ilverson L4R (small head adapter). The batches are allowed to cool to room temperature, while stirring continuously. The viscosity measurements are taken after 1 to 3 hours of mixing and after 22 hours, when using a Haake viscometer at 500 xs
Results
No significant change in viscosity is observed during a period of 22 hours. This is a very desirable property in the preparation of FDDF. This property improves the efficiency of the production and reduces the asperity due to waste.
EXAMPLE 6 Comparative stability study between Paselli BC and Gelatine
Formulation of Quantity (g) by weight modified starch
Paselli BC is a pre-gelatinized acetylated phosphatized di-starch commercially available from Croda Colloids, Ltd of Cheshire, England.
Gelatine formulation Gelatin and mannitol are added to the apex of the purified water, and heated to 60 ° C to effect the solution. The mixture is subsequently cooled to 25 ° C before dosing.
Formulation of modified starch Mannitol and Paselli BC are mixed dry and then gradually added to the vortex of purified water at room temperature. The resulting mixture is subsequently homogenized when using Silverson L4R (small head adapter) for approximately 1 minute.
The mixtures are dosed in PVC / PVdC vials, 16 millimeters in diameter, and 500 milligrams in weight of the filling when using a Hamilton Microlab M dispenser. The vials are frozen in an ice gas stream before being dehydrated by freezing the Change the temperature rapidly from -10 ° C to + 20 ° C at a pressure of 0.5 mbar. The units are placed, unsealed, in stable cabinets at 40 ° C with a relative humidity of 75 percent for 20 hours, the diameters of the units are taken after this period of time.
Results
It can be seen that the FDDF that uses the modified starch has a 50 percent decrease in the amount of shrinkage on the
Conventional FDDFs contain gelatin. This is a surprising and unexpected result.
EXAMPLE 7 Comparative - Gelatin against modified starch FDDF An article entitled 'Drug Delivery Products and the Zydis Fast Dissolving Dosage Form' by H. Seagers et al., J. Pharm Pharma col., 1998, discusses the problems associated with highly water soluble drugs in an FDDF. The ZydisS is the registered trademark of R.P. Scherer Corporation, Basking Ridge, N.J., USA. Seagers et al., It is recognized that the dose of water soluble drugs are generally limited to a higher value of approximately 60 milligrams per dosage form. The dose is governed by the behavior of the drug during the freezing process and its dehydration characteristics. Eutectic mixtures can be formed that can not be adequately frozen or can melt at higher temperatures that are used in the freeze-drying process. It is also possible that the dissolved drug may form an amorphous solid during freezing and that this solid may collapse during the dehydration process due to the sublimation of the ice and the loss of the support structure. It is known that the collapse of the structure that is formed by the water-soluble drugs is decreased by the inclusion of a glass-forming excipient. These materials are sometimes known as matrix forming agents. These materials induce crystallinity and therefore rigidity in amorphous products. Another methodology is to agglutinate the water soluble compound in an ion exchange resin to form a water insoluble complex. Another technique is a non-aqueous dosage solution of active ingredient in preformed FDDF units of a placebo. The organic solvent is then evaporated and the recrystallized drug is deposited in the pores of the Zydis matrix. Another technique that is known to overcome this problem of the highly water soluble active ingredients is to reduce the proportion of excipient for drug and therefore increase the weight of filling of the vesicle. This effectively dilutes the effect of the soluble active ingredient, by having the same dose of the drug, but a greater amount of excipients being present.
This potential solution has obvious disadvantages in that it requires larger amounts of excipients, a larger dosage form which is 'less patient friendly', and a decrease in production in manufacturing due to size limitations. It is also known that solubility of the drug can be changed by pH manipulation It is known that reduced solubility facilitates the incorporation of a higher dose of the active ingredient into an FDDF One aspect of the present invention resides in the discovery that the use of essentially free gelatin FDDF using a modified starch material may incorporate higher levels of water soluble drugs than the conventional gelatin system This example is submitted to demonstrate this unexpected result In this example, three (3) highly water soluble active ingredients are formulated in a FDDF These active solubilities in water are shown below:
Diclofenac sodium - 1:30 water Pravastatin sodium - 1: 3 water HCl of phenylpropanolamine - 1: 2.5 water
The following samples are prepared in accordance with Table 1.
TABLE 1 (All values are by weight,
provides 12.5 mg of active ingredient in a 500-milligram fill. provides 10.0 mg of active ingredient in a 500-milligram fill. provides 12.5 mg of active ingredient in a 500-milligram fill.
Samples 1, 3 and 5 (samples containing gelatins) are prepared by adding gelatin and mannitol to the vortex of the purified and agitated water. The mixture is then heated to a temperature of 60 ° C (+ 1 ° C) to place the gelatin and mannitol in solution. The solution is subsequently cooled to a temperature of 24 ° C (+ 1 ° C) and the required amount of active material is incorporated. Each lot is kept for a minimum of one (1) hour before dosing in the vesicular packaging. Samples 2, 4 and 6 (the modified starch samples) are prepared by adding the starch and mannitol to the clean, dry lab bench and dry mixing the materials with a spatula. The purified water is subsequently added to this mixture and homogenized by using the Silverson L4R homogenizer - with small head adaption at half speed for a period of two (2) minutes. The active material indicated is then added to this solution and left for a minimum of one (1) hour before dosing. No warm-up of these skills is required or carried out. Each sample is dosed to a package of 20 vesicles when using Hamilton Microlab, which delivers 500 milligrams of the mixture (+22) into the bags of the aluminum vesicles. The vesicular packaging is then frozen at a temperature of -110 ° C using liquid nitrogen with a residence time of 3.2 minutes. The frozen samples are subsequently stored at -25 ° C before being dehydrated by freezing. Dehydration by freezing is carried out by using a temperature cycle of -10 ° C to 10 ° C at
0. 5 mbar The samples are then dehydrated overnight on the same day of manufacture. After dehydrating by freezing, each package is removed and inspected. Each sample bladder is inspected for cracking. This cracking is visually apparent from an inspection of the FDDF and it is determined that 90 percent of Sample 1 shows signs of evidence of cracking while 0 percent is evident for Sample 2 (the comparative example that contains modified starch) . The
Sample 3, which contains the gelatin, shows evidence of a cracking ratio of 45-50 percent while the starch-based formula, of Sample 4, shows no cracking. Sample 5 containing 2.5 weight percent of phenylpropanolamine and 4 weight percent of gelatin shows evidence of a cracking ratio of 60-70 percent. This means that 60-70 percent of the 20 vesicle fillers for this sample show evidence of cracking and crumbles when attempting to withdraw from the vesicular packing. By contrast, the use of starch in Sample 6 shows evidence only of a 10-20 percent cracking ratio. This experiment readily demonstrates that the use of the modified starch in a FDDF allows high levels of active ingredients highly soluble in water to be incorporated into FDDF without experiencing cracking and degradation of physical stability as observed with conventional gelatin formulations
EXAMPLE 8 Comparative From the work carried out in Example 7, it is evident that the use of the modified starch in a FDDF allows a higher loading of the dosage form without the occurrence of cracking and / or physical failure. An effort was made to determine how much additional material should be required to prepare a gelatin-based FDDF containing the same amount of active ingredient, per dosage form. In essence, this experiment was carried out to determine whether gelatin-based formulas containing highly soluble active ingredients can be prepared without melting (absorption of water vapor and degradation of physical stability) and cracking problems. The following formulations are prepared:
TABLE II (All are in% weight)
These samples are manufactured as set forth in Example 7, except that a 750 milliliter fill is used. After the removal of samples from dehydration by freezing, the visual inspection? results in none of the samples containing cracks. This Example demonstrates that greater dosage units are required if gelatin is used in the preparation of rapid dissolution dosage forms. This unexpected result is advantageous in that the smaller dosage forms used by the modified starch enhance patient compliance and reduce the cost of manufacturing.
INDUSTRIAL APPLICATION This invention relates to rapid dissolution dosage forms for oral administration. The advantages of rapid dispersion dosage forms include the lingual, sublingual or buccal administration of the drugs. The current, and more commercially popular form is a rapidly soluble solid dosage form that is made by aliquoting a slurry of a therapeutic agent, solvent, gelatin, and other excipients in preformed depressions. Then the liquid freezes and the solvent is removed by sublimation, typically by freeze-drying. The resulting tablet has a matrix of open pores that dissolves rapidly on contact with saliva. The use of conventional FDDFs have certain drawbacks such as 1) the use of gelatin derived from a mammal; 2) the limited load of active ingredients highly soluble in water in the FDDF; 3) lack of mechanical force; 4) unpleasant taste; 5) inability to provide homogeneity to the mixture; 6) inability to prevent sedimentation of active particles; and 7) a minimum solution in cold water. The present invention advances the state of the art of FDDF upon discovering that certain modified starches can be used FDDF having improved physical stability; an unexpected ability to contain higher loads of drugs highly soluble in water; an improved flavor; improved physical stability (resistance to moisture uptake and subsequent shrinkage when compared to gelatin matrix systems); and a substantial reduction in the sedimentation rate of the active particles in the mixture. It should be understood that the specification and the examples are illustrative but not limiting of the present invention and that other embodiments within the spirit and scope of the invention suggest themselves to those skilled in the art. It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (9)
1. A solid fast dispersing dosage form designed to rapidly release an active ingredient within the oral cavity, characterized in that the dosage form is essentially free of mammalian gelatin and comprises: a) at least one active ingredient; b) at least one modified starch at a concentration ranging from 20 to 90 weight percent; and c) at least one matrix forming agent; wherein the solid dosage form can be obtained by removing a solvent from a mixture comprising the active ingredient, the modified starch and the matrix forming agent.
2. The fast dispersing solid dosage form according to claim 1, characterized in that the modified starch is selected from a group consisting of starches whose hydroxyl groups have been esterified, d-hydroxypropyl phosphate starch, an enzymatically modified starch, a pregelatinized phosphatized di-starch, hydroxyethyl starch, an acetylated and pregelatinized phosphonated dialmidon and a pregelatinized purified starch.
3. The fast dispersing solid dosage form according to claim 1, characterized in that it comprises from 50 percent to 90 percent by weight of the modified starch.
4. The fast dispersing solid dosage form according to claim 1, characterized in that the modified starches are easily soluble or dispersible in water at room temperature.
5. The fast dispersing solid dosage form according to claim 1, characterized in that the mixture of active ingredient, modified starch and matrix forming agent exhibit a sufficiently consistent viscosity over a period of time of about 24 hours.
6. The fast dispersing solid dosage form according to claim 1, characterized in that the preferred solvent is water.
7. The fast dispersing solid dosage form according to claim 1, characterized in that the preferred matrix forming agent is mannitol.
8. The fast dispersing solid dosage form according to claim 1, characterized in that it can also contain coloring agents, flavoring agents, excipients, multiple therapeutic agents and the like.
9. The fast dispersing solid dosage form according to claim 1, characterized in that removal of the solvent from the mixture is preferably carried out by freeze-drying. FAST DISPERSION DOSAGE FORMS GELATIN FREE SUMMARY OF THE INVENTION The present invention relates to solid dosage forms and rapid dispersion which preferably dissolve in the oral cavity within sixty (60), or more preferably within thirty (30), more preferably within ten (10) seconds. A novel feature of the solid dosage forms according to the invention resides in the fact that the composition is essentially free or absolutely free of mammalian gelatin. It has been found that the use of certain modified starches in concentrations ranging from 20 to 90 by weight of the solid dosage form prepares dosage dosages which are mechanically and chemically stable and which are capable of delivering higher concentrations of an active ingredient than the gelatin-based fast dispersing solid dosage forms that are used above. Moreover, the solid dosage forms according to the invention can be obtained by removing a solvent, such as water, from a mixture comprising an active ingredient, a modified starch and a matrix-forming agent by means of freeze-drying. .
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB9901819.4 | 1999-01-27 |
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MXPA01007569A true MXPA01007569A (en) | 2002-05-09 |
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