HK1117072A - Quinine-containing controlled-release formulations - Google Patents

Description

Controlled release preparation containing quinine

Technical Field

The application relates to a controlled-release quinine preparation and a preparation method thereof, and also relates to application of the controlled-release quinine preparation in preparing a medicament for treating or preventing malaria, leg spasm or babesiosis, and the treatment or prevention is realized by applying the controlled-release quinine preparation. The controlled-release formulation of quinine may help reduce or eliminate the adverse side effects typically caused by administration of quinine.

Background

[0001] Malaria is a parasitic disease caused by Plasmodium falciparum (p.falciparum), Plasmodium vivax (p.vivax), Plasmodium ovale (p.ovale) and Plasmodium malariae (p.malariae) belonging to the Plasmodium species. Malaria parasites cause intermittent episodes of chills and fever that affect most organs and systems such as red blood cells, kidneys, liver, spleen and brain. According to the World Health Organization (WHO), Malaria is estimated to be infected by 5 hundred million each year, 2-3 million of the people are long-term Malaria patients (see Roll Back Malaria, world health organization: www.rbm.who.int/cmc _ upload/0/000/015372/RBMINFOSHEET _1.htm), and 300 million people die each year. Total survey data indicate that infection with Plasmodium falciparum, if untreated, or improperly treated, is more fatal, with 25% of immunocompromised adults dying within 2 weeks of the first attack (Taylor TE, Strickland GT. Malaria. In: Strickland GT, ed. Hunter's radiological Medicine and ignition in diseases, 8. Philadelphia, PA: W.B.Saunders Company; 2000). A large number of cases are common in central america, south america, asia and africa. Known antimalarial drugs include 9-aminoacridines (e.g., quinacrine), 4-aminoquinolines (e.g., amodiaquine, chloroquine, hydroxychloroquine), 8-aminoquinolines (e.g., primaquine, quintocet), biguanides with dihydrofolate reductase inhibition (e.g., chlorpromoguanidine, cyclochloroguanidine, chloroguanidine), diaminopyrimidines (e.g., pyrimethamine), quinine salts, sulfones such as dapsone, sulfonamides, and antibiotics such as tetracycline.

[0002] Quinine (cinchonin-9-ol, 6' -methoxy, (8 α, 9R) -) is an antiprotozoal and antimyotonic drug, and can be used for treating malaria caused by plasmodium species, treating and preventing nocturnal sleep leg muscle spasm, and treating babesiosis caused by Babesia microti (Babesia microti). Quinine has a structure similar to quinidine, which is also an antiprotozoal drug and is useful as an antiarrhythmic agent. Quinidine causes dose-related QT interval prolongation, which in the electrocardiogram can be used to reflect ventricular repolarization delays. QT prolongation is associated with an increased risk of ventricular arrhythmias. While quinine is a diastereoisomer of quinidine, it does not cause QT prolongation to the extent of quinidine, however, patients with a history of arrhythmia or QT prolongation should be cautiously treated with quinine in situations where there may be a risk of arrhythmia.

[0003] There remains a need in the art for the development of quinine formulations that have desirable therapeutic effects in certain diseases, such as malaria, while minimizing the adverse side effects associated with quinine administration.

Disclosure of Invention

[0004] Controlled release quinine formulations and quinine mixture formulations are provided herein, as well as methods of using the controlled release formulations for therapeutic purposes. Exemplary therapeutic objectives include: treating or preventing malaria; leg spasms, including nocturnal sleep leg spasms, idiopathic leg spasms, and exercise-induced spasms; and babesiosis caused by babesia microti.

[0005] In one embodiment, a controlled release formulation comprises a therapeutically effective amount of quinine, wherein administration of the controlled release formulation reduces or eliminates adverse side effects associated with the use of an immediate release formulation of quinine.

[0006] In another embodiment, a method of reducing the severity of, or eliminating, adverse side effects associated with the use of an immediate release formulation of quinine comprises administering to a patient a controlled release formulation of quinine.

Drawings

[0007] FIG. 1: mean plasma concentrations and QTc measurements of oral single dose quinine sulfate 24 hours after administration under fasting conditions.

[0008] FIG. 2: mean plasma concentrations and QTc measurements of oral single dose quinine sulfate 24 hours after administration under fed conditions.

[0009] FIG. 3: plasma mean concentration and QTc measurements of an oral single dose of 324mg quinine sulfate 24 hours after administration under fasting conditions.

[0010] FIG. 4: plasma mean concentration and QTc measurements of an oral single dose of 648mg quinine sulfate 24 hours after administration under fasting conditions.

Detailed Description

[0011]Optimal efficacy is seen if effective plasma levels are achieved when treated with quinine. In addition, peak plasma value (C)_max) Should be as low as possible to reduce the incidence and severity of possible adverse side effects such as QT prolongation adverse events and the like. Quinine dosage forms that are administered once a day and that maintain effective plasma levels for 8-24 hours are desirable for patient or healthcare personnel convenience.

[0012] It has been found that a controlled release dosage form of quinine or a pharmaceutically acceptable salt thereof, administered at the same dose concentration, reduces the adverse side effects often associated with immediate release dosage forms of quinine. Described herein are controlled release formulations of quinine, methods of making and methods of using the same.

[0013] Controlled-release formulations of quinine can reduce the adverse side effects caused by high doses of quinine or even therapeutic doses of quinine. Such adverse side effects that may be reduced include, for example, cinchona poisoning, tinnitus, blurred vision, thrombocytopenia, granulomatous hepatitis, rash, acute interstitial nephritis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS), QT interval prolongation, QTc interval prolongation, agranulocytosis, hypoprothronemia, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, headache, diplopia, thought disorder, mental state changes, seizures, coma, pruritis, skin flushing, sweating, episodic facial edema, rash, urticaria, erythema multiforme, purpura, light sensitivity, contact gangrene, acromelittic gangrene, cutaneous vasculitis, asthma, tachycardia, arrhythmia, ventricular premature beats (PVCs), PVCs associated nodal beats, normal, QRS and QT intervals Ventricular fibrillation, arrhythmia, nausea, vomiting, abdominal pain, diarrhea, visual disorders including sudden visual loss, blindness, diminished visual field, fixed nipple extension, color vision disorders, hearing loss, and deafness.

[0014] Herein, the QT prolongation time or magnitude (representing the time course from activation to recovery of the ventricular myocardium) as determined by the surface Electrocardiogram (EKG) from the onset of the QRS complex to the end of the T wave measured after administration of the controlled release formulation of quinine is shortened compared to the immediate release formulation of quinine (e.g., administration of TID). QT values are corrected by heart rate to "QTc". QTc is generally considered abnormal for more than about 0.44 seconds, although age-and sex-specific QTc outliers differ from this value.

[0015]Herein, "wherein Administration of a controlled release formulation does not cause significant QT Prolongation according to the criteria of the U.S. Food and Drug Administration" criteria mentioned in this sentence are referred to in the document "guidelines for Industry, E14 Clinical Evaluation of QT/QTc alternation and Proarrhythmic Power for non-antibiotic Drugs, U.S. department of Health and human services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biological Evaluation and Research (CBER)", published by the U.S. patenthttp://www.fda.gov/cder/guidance/index.htm。

[0016] Controlled release formulations of quinine or a pharmaceutically acceptable salt thereof produce plasma levels of quinine that are more stable than immediate release formulations, and yield the active metabolite 3-hydroxyquinine. While a more stable plasma level may shorten the time course of prolonged QT or QTc intervals that would otherwise be caused by an increase in quinine dose or "dose dumping". In addition, the more stable plasma levels may also reduce or avoid other adverse side effects as outlined above.

[0017] Another advantage of controlled release formulations, particularly sustained release formulations, is that patient compliance is improved and that the dosage form count and packaging is reduced, making it easier for the pharmacist to dispense. At present, the sustained-release quinine sulfate oral tablet for treating plasmodium falciparum or babesiosis is generally taken at intervals of 600-650mg every 8 hours. If the daily dose is reduced, and potentially some adverse side effects are reduced or eliminated, the patient will more closely follow the prescribed regimen. Such increased compliance with the regimen increases the success of the treatment for the particular disease being treated.

[0018] In general, suitable sustained release dosage forms include wax or polymer coated tablets, caplets, or drug cores; a controlled release matrix; or a combination comprising at least one of the foregoing. Other oral dosage forms include, for example, suspensions, emulsions, orally disintegrating tablets including effervescent tablets, chewable tablets, enteric coated tablets, soft capsules, hard capsules, enteric coated capsules, coated granules, enteric coated granules, controlled release granules, osmotic pumps, and the like. Suitable sustained release formulations for quinine or a salt thereof include, for example, those described in the following documents: stationary Release medicines, Chemical technology review No.177.Ed.J.C.Johnson.Noyes Data Corporation 1980 and Controlled Drug Delivery, Fundamentals and Applications, 2nd edition.Eds.J.R.Robinson, V.H.L.Lee.MercDekker Inc.New York 1987. Other dosage forms are described in U.S. Pat. Nos. 5,102,666 and 5,422,123.

[0019] The term "active agent" refers to a compound, element or mixture that is administered to a patient alone or in combination with another compound, element or mixture that directly or indirectly exerts a physiological effect on the patient. This indirect physiological effect may be produced by a metabolite or other indirect mechanism. When the active agent is a compound, the compound, salts of the compound, solvates (including hydrates) of the free compound or salt, crystalline, non-crystalline, and any polymorphic form of the compound are contemplated herein.

[0020]"pharmaceutically acceptable salts" include derivatives of quinine in which the parent compound is modified to form a non-toxic acid salt, and further refers to pharmaceutically acceptable solvates (including hydrates) of said compound and said salt, and all crystalline, amorphous and polymorphic forms are intended. Pharmaceutically acceptable salts include, for example, but are not limited to, inorganic or organic acid salts and the like, as well as combinations comprising at least one of the foregoing. Such pharmaceutically acceptable salts include, for example, non-toxic salts formed from non-toxic inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like. Pharmaceutically acceptable organic salts include those formed from, for example, acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, methanesulfonic, ethanesulfonic, benzenesulfonic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethyldisulfonic, oxalic, isethionic, HOOC- (CH) sulfonic₂)_n-COOH (n is 0 to 4), etc. Specific quinine salts include quinine sulfate, quinine hydrochloride, quinine dihydrochloride, and hydrates thereof.

[0021] Herein, unless otherwise specifically indicated, the term "quinine" includes all pharmaceutically acceptable salt forms, crystalline forms, amorphous forms, polymorphic forms, solvates and hydrates thereof. As used herein, quinine sulfate refers to cinchonin-9-ol, 6 '-methoxy, (8 α, 9R) -, sulfate (2: 1) or cinchonin-9-ol, 6' -methoxy, (8 α, 9R) -, sulfate (2: 1) hydrate, unless otherwise specified.

[0022] "bioavailability" refers to the degree or rate at which an active agent is absorbed by a living system or is present at a site of physiological activity. For an active agent intended to enter the bloodstream by absorption, bioavailability data for a particular formulation is determined and the portion of the administered dose that is absorbed into the systemic circulation can be estimated. "bioavailability" can be characterized by one or more pharmacokinetic parameters.

[0023] "dosage form" refers to the unit of administration of an active agent. Dosage forms include, for example, tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalation forms, transdermal forms, and the like. The quinine preparation can be administered orally, buccally, by injection or transdermally.

[0024] By "oral dosage form" is meant to include dosage forms that are, or are intended to be, orally administered as specified. Oral dosage forms may or may not include multiple subunits, e.g., microcapsules or mini-tablets, packaged for single dose oral administration, and may be solid or liquid.

[0025] An "effective amount" or "pharmaceutically effective amount" of an active agent refers to an amount of the active agent sufficient to produce a therapeutic effect in a patient. The effective amount will vary with the age and general health of the individual, the particular active agent, and like factors. Therefore, it is often not possible to specify an exact "effective amount" but a suitable "effective" amount for use in any single case can be determined by one of ordinary skill in the art based on routine experimentation.

[0026] "efficacy" refers to the ability of an active agent administered to a patient to produce a therapeutic effect in the patient.

[0027] By "patient" is meant a human or non-human animal in need of medical treatment. Medical treatment may include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. The patient in certain embodiments is a human. "health care workers" include workers in the healthcare field, physicians, pharmacists, physician assistants, nurses, assistants, paramedics (which may include family members or guardians), emergency medical personnel, and the like.

[0028] The term "treating" refers to reducing the severity of symptoms or reducing the frequency of attacks, eliminating symptoms or underlying causes, preventing symptoms or their underlying causes, and improving or curing the injury.

[0029] "product" or "pharmaceutical" refers to the active agent dosage form, and may also refer to the active agent and its packaging.

[0030] "safety" refers to the incidence or severity of adverse events resulting from administration of an active agent, including adverse effects resulting from patient-related factors (such as age, sex, ethnicity, race, disease of interest, renal or hepatic dysfunction, comorbidities, genetic characteristics such as metabolic status, or environment) and active agent-related factors (such as dose, plasma levels, exposure time, or concomitant medication).

[0031] "Release form" includes immediate release, controlled release and sustained release forms. Certain released forms may be characterized by their dissolution profile. Herein, the dissolution profile refers to the release of the active ingredient as a function of time. The dissolution profile may be measured using the drug release test <724> which comprises the standard test USP28 (test <711>), or other test methods or conditions may be employed. The curve characteristics are expressed in terms of the selected test conditions. This allows the dissolution profile to be obtained under preselected device types, shaft speeds, temperatures, volumes and dissolution medium pH conditions.

[0032] The first dissolution profile may be measured at a pH level near the stomach. The second dissolution profile may be measured at a pH level near a point in the intestine or at multiple pH levels near multiple points in the intestine.

[0033] The pH of the stomach can be simulated with a strongly acidic pH, and the pH of the intestine can be simulated with a weakly acidic to basic pH. "strongly acidic pH" means a pH of about 0 to 4. By "weakly acidic to basic pH" is meant a pH greater than about 4 to about 7.5, specifically greater than about 6 to about 7.5. A pH of about 1.2 may be used to mimic the pH of the stomach. The pH of the intestine may be simulated with a pH of about 6-7.5, specifically, with a pH of about 6.8.

[0034]"pharmacokinetic parameter" means an in vivo characteristic of an active agent (or a surrogate marker of an active agent) over a period of time, such as plasma concentration (C), C_max、C_n、C₂₄、T_maxAnd AUC. "C_max"is the measured concentration of the active agent in the plasma at the point of highest concentration. "C_n"is the measured concentration of the active agent in the plasma after about n hours of administration. "C₂₄"is the measured concentration of the active agent in the plasma after about 24 hours from administration. "T_max"means the time at which the measured concentration of active agent in the plasma reaches a maximum after administration of the active agent. "AUC" refers to the measured area from one time point to another under the plot of measured concentration (typically plasma concentration) of an active agent versus time. For example, AUC_0-tRefers to the area under the plasma concentration versus time curve from time 0 to time t. AUC_0-∞(AUC_∞) Or AUC_0-INF(AUC_inf) Refers to the calculated area from time 0 to time infinity under the plasma concentration versus time curve.

[0035] By "immediate release" is meant a traditional or uncontrolled release form in which the active agent is released in an amount of about 75% or greater within 2 hours of administration, specifically within 1 hour of administration. In addition, the "immediate release" formulations are substantially free of release blockers.

[0036] "controlled release" refers to a dosage form in which the release of the active agent is controlled or modified over a period of time. "controlling" may for example refer to extending or delaying the release at a particular time. In addition, "controlled" may also mean that the active agent is released over a longer period of time than it takes to release its immediate release dosage form, i.e., at least over a few hours.

[0037] "sustained release" includes release of the active agent after administration at a rate that maintains steady state blood (e.g., plasma) levels over a therapeutic range for at least about 8 hours, specifically at least about 12 hours, and more specifically at least about 24 hours. The term "steady state" means that after a plasma level of a given active agent is reached, that level will continue to be maintained and subsequent doses of the agent are at or above the lowest therapeutically effective level for the given active agent.

[0038] By "delayed release" is meant a time delay before significant plasma levels of the active agent are achieved. Delayed release formulations of the active agent may avoid an initial burst of the active agent, or may avoid release of the active agent in the stomach, allowing the active agent to be absorbed in the small intestine.

[0039] Sustained release dosage forms refer to suitable dosage forms that provide controlled release of quinine over a sustained release period (e.g., 8 hours, 12 hours, 24 hours). The quinine sustained-release dosage form can release the active agent at a rate that is independent of pH (e.g., about 1.2-7.5). Alternatively, the sustained release dosage form may release quinine at a rate that is pH dependent, e.g., at a release rate at pH1.2 and a high release rate at pH 7.5. In particular, sustained release dosage forms avoid dose dumping after oral administration. The sustained release oral dosage form can be prepared into a preparation with prolonged action period of quinine after 1 time or 2 times of medication in 1 day.

[0040] There are several methods for preparing quinine sustained release formulations. Typical dosage forms include polymer matrices containing quinine, coated tablets, coated particles, osmotic pumps, depot dosage forms (depot forms), and the like. As will be discussed below.

[0041] In general, sustained release dosage forms include a release retarding material. Such release retarding materials may be in the form of a matrix or a coating, for example. The quinine in the sustained release dosage form may be, for example, quinine particles mixed together with a release retarding material. A release retarding material is a material that allows the release of an active agent at a constant rate in an aqueous medium. By selectively selecting a release-retarding material in combination with other such properties, a desired in vitro release rate can be achieved.

[0042] Release retarding materials include, for example, acrylic polymers, alkyl celluloses, shellacs, zeins, hydrogenated vegetable oils, hydrogenated castor oils, polyvinylpyrrolidones, vinyl acetate copolymers, polyethylene oxides, and combinations comprising at least one of the foregoing materials. The sustained release oral dosage form may contain from about 1% to about 80% by weight of the release retarding material based on the total weight of the dosage form.

[0043] Suitable acrylic polymers that may be used as release retarding materials include, for example, acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly (acrylic acid), poly (methacrylic acid), methacrylic acid-alkylamide copolymers, poly (methyl methacrylate), poly (methacrylic anhydride), methyl methacrylate, polymethacrylates, poly (methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, glycidyl methacrylate copolymers, and combinations comprising at least one of the foregoing polymers. The acrylic polymer may comprise a methacrylate copolymer containing a low content of quaternary ammonium groups, fully polymerized with a methacrylate, of acrylic acid as described in NF XXIV.

[0044] Suitable alkyl celluloses include, for example, methyl cellulose, ethyl cellulose, and the like. It will be appreciated by those skilled in the art that other cellulose polymers, including other alkyl cellulose polymers, may replace some or all of the ethyl cellulose.

[0045] Other suitable release retarding materials include neutral or synthetic waxes, fatty alcohols (such as lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, or specifically cetostearyl alcohol), fatty acids including fatty acid esters, fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated fatty acids, hydrocarbons, normal waxes (normal wax), stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials having a hydrocarbon backbone, and combinations comprising at least one of the foregoing materials. Suitable waxes include beeswax, sugar wax (glycowax), castor wax, carnauba wax, and waxy materials (e.g., materials that are typically solid at room temperature and have a melting point of about 30-100 ℃), as well as combinations comprising at least one of the foregoing waxes.

[0046]In other embodiments, the release retarding material may comprise digestible, long (e.g., C)₈-C₅₀In particular C₁₂-C₄₀) Substituted or unsubstituted hydrocarbon chains, such as fatty acids, fatty alcohols, fatty acid glycerides, vegetable oils, waxes, and combinations comprising at least one of the foregoing. Hydrocarbons having melting points between about 25-90 c may be used. In particular, long chain hydrocarbon materials such as fatty alcohols may be used. The oral dosage form may contain about 60% by weight of digestible long chain hydrocarbons based on the total weight of the dosage form.

[0047] In addition, the sustained-release base may contain about 60% by weight of polyalkylene glycol.

[0048] In addition, the release retarding material may also comprise polylactic acid, polyglycolic acid, or a copolymer of lactic acid and glycolic acid.

[0049] In addition, the release retarding material may also include, for example, croscarmellose sodium, cross-linked hydroxypropyl cellulose, high molecular weight hydroxypropyl methylcellulose, carboxymethyl starch, potassium methacrylate/divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone, high molecular weight polyvinyl alcohol, methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight polyvinyl alcohol, polyethylene glycol, non-cross-linked polyvinylpyrrolidone, medium viscosity hydroxypropyl methylcellulose, medium viscosity polyvinyl alcohol, combinations thereof, and the like.

[0050] Optionally, a controlled release agent that affects the release characteristics of the release retarding material may be used. The controlled release agent can be used, for example, as a pore-forming agent. The porogen may be an inorganic or organic material, including materials that can be dissolved, extracted, or filtered out in the environment of use. The porogen may comprise one or more hydrophilic polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polycarbonates comprised of linear polycarbonates wherein the carbonate groups in the polymer chain are repeated, and combinations comprising at least one of the foregoing controlled release agents.

[0051] The release retarding material may optionally also include other additives such as corrosion-promoting agents (e.g., starch and glue) and/or semipermeable polymers. In addition to the above ingredients, the sustained-release formulation may contain appropriate amounts of other materials such as diluents, lubricants, binders, granulation aids, coloring agents, flavoring agents, and flow agents, which are conventionally used in the pharmaceutical field. The release retarding material may also include an exit means (exitmeans) comprising channels, openings, etc. The channel may have any shape, such as circular, rectangular, square, oval, irregular, and the like.

[0052] Sustained release dosage forms containing quinine or a salt thereof and a release retarding material may be prepared by suitable techniques for preparing the active agent as described in detail below. The quinine or salt thereof and the release retarding material may be prepared, for example, by wet granulation, melt extrusion, and the like. Other hydrophilic materials are added to facilitate the preparation of the sustained-release preparation.

[0053] The quinine or salt thereof in the sustained-release dosage form may include a plurality of matrices (particles, e.g., microparticles) containing the active agent, the matrices having a sustained-release coating thereon comprising a release retarding material. Thus, sustained release formulations can be prepared in conjunction with multiparticulate systems such as beads, ion exchange resin beads, spheroids, microspheres, kernels, pellets, granules and the like to achieve the desired sustained release effect of the quinine or salt thereof. The multiparticulate system may be presented in a capsule or other suitable unit dosage form.

[0054] In some cases, more than one multiparticulate system may be used, each system having different characteristics, such as pH dependent release, release time in various media (e.g., acids, bases, intestinal fluid mimicking fluids), in vivo release, size and composition.

[0055] In some cases, the nodularizer and quinine, or a salt thereof, may be nodulized together into spheroids. Such formulations are, for example, non-tactile microcrystalline cellulose and hydrous lactose. In addition, these spheroids may also contain a water-insoluble polymer, and specifically may contain an acrylic polymer, an acrylic copolymer such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose. In such a formulation, the sustained release coating will generally include a water-insoluble material, such as a wax, either alone or in admixture with a fatty alcohol or shellac or zein.

[0056] Spheroids or beads coated with quinine or a salt thereof may be prepared, for example, as follows: the active agent is dissolved or dispersed in a solvent and the solution is then sprayed onto a substrate such as sugar spheres NF (18/20 mesh) using a Uurster insertion device. In addition, other ingredients may be added prior to coating the beads to aid in binding of the quinine or salt thereof to the matrix, and/or to color the resulting beads, etc. The resulting matrix-active agent coating may be further coated with a release material, as the case may be, to separate the therapeutically active agent from the next coating layer, such as a release retarding material. The separator is, for example, a material containing hydroxypropylmethylcellulose. However, film formers known in the art may be used.

[0057] To obtain a sustained release quinine or salt thereof with sufficient therapeutic effect for a prolonged period of time, the matrix containing the active agent may be coated with an amount of release retarding material sufficient to increase the weight by about 2-30 wt%, specifically about 5-25 wt%, and more specifically about 7-20 wt%, although the coating may be larger or smaller depending on the physical characteristics of the active agent used and the desired release rate, etc. In addition, more than one release retarding material, as well as other various pharmaceutical excipients, may also be used in the coating.

[0058] Thus, the release retarding material may be a film coating comprising a dispersion of a hydrophobic polymer. Solvents used in the release-retarding coating include pharmaceutically acceptable solvents such as water, methanol, ethanol, methylene chloride, and combinations comprising at least one of the foregoing solvents.

[0059] Additionally, the sustained release profile (in vivo or in vitro) of quinine or a salt thereof may be altered, for example, by using more than one release retarding material, by altering the thickness of the release retarding material, by changing the particular release retarding material used, by changing the relative amount of release retarding material, by changing the manner in which the plasticizer is added (e.g., when the sustained release coating is derived from an aqueous dispersion of a hydrophobic polymer), by changing the relative amounts of plasticizer and retarding material, by adding other ingredients or excipients, by changing the method of preparation, and the like.

[0060] The sustained release formulation preferably releases quinine or a salt thereof slowly, for example, when swallowed and exposed to gastric fluid, followed by exposure to intestinal fluid. The sustained release characteristics of the above-described formulations can be altered, for example, by varying the amount of retarding agent, such as hydrophobic material, varying the relative amounts of plasticizer and retarding material, adding other ingredients or excipients, varying the method of preparation, and the like.

[0061] A typical dosage form having a coating of a release retarding material may comprise quinine mixed with a water-soluble film-forming polymer. Soluble film-forming polymers which may be used are those which have an apparent viscosity of from 1 to 100mPa.s when dissolved in a 2% aqueous solution at 20 ℃. For example, such soluble film-forming polymers may be selected from alkyl celluloses such as methylcellulose, hydroxyalkyl celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkyl alkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcellulose such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcellulose esters, starches, colloidal starches such as sodium carboxymethyl gum starch, chitin derivatives such as chitosan, polysaccharides such as alginic acid and its alkali metal and ammonium salts, carrageenan, galactomannan, traganth, agar, acacia, guar gum and xanthan gum, polyacrylic acids and salts thereof, polymethacrylic acids and salts thereof, methacrylate copolymers, polyvinyl alcohol, Polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymers, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. Other medicinal polymers having physical and chemical properties similar to those of the above polymers are also suitable.

[0062] Specific water-soluble film-forming polymers are, for example, hydroxypropylmethylcellulose, polymethacrylates, hydroxypropylcellulose or povidone, more specifically Hydroxypropylmethylcellulose (HPMCs). Sufficient hydroxypropyl and methoxy groups in HPMCs render them water soluble. HPMC having a degree of substitution of from about 0.8 to about 2.5 methoxy groups and a molar substitution of from about 0.05 to about 3.0 hydroxypropyl groups are generally water soluble. The degree of substitution with methoxy groups means the average number of methyl ether groups contained in each anhydroglucose unit in the cellulose molecule. The hydroxypropyl molar substitution refers to the average number of moles of propylene oxide reacted with each anhydroglucose unit of the cellulose molecule. Suitable HPMC's include HPMC of viscosity of about 1-100mPa.s, in particular about 3-15mPa.s, and even more particularly about 5 mPa.s.

[0063] The weight ratio of the active ingredients to the medicine is as follows: the water-soluble film-forming polymer is between about 17: 1 and 1: 5, specifically between about 10: 1 and 1: 3, and more specifically between about 7: 1 and 1: 2.

[0064] The particles generally comprise (a) a centrally located round or spherical core, (b) a layer or coating film comprising a water-soluble film-forming polymer and quinine or a salt thereof, (c) optionally a polymeric barrier layer, and (d) a release-retarding material coating. The core has a diameter of about 250-.

[0065] Materials suitable for use as the core include pharmaceutical materials of suitable size and firmness. Such materials are, for example, polymers, such as plastic resins; inorganic substances such as silica, glass, hydroxyapatite, salts (sodium or potassium chloride, calcium or magnesium carbonate), and the like; organic substances such as activated carbon, acids (citric acid, fumaric acid, tartaric acid, ascorbic acid, etc.), and sugars and derivatives thereof. Particularly suitable materials are sugars, such as monosaccharides, oligosaccharides, polysaccharides and derivatives thereof, for example glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, starches (corn starch, rice starch, potato starch, wheat starch, tapioca starch) and the like.

[0066] The combination of the water-soluble film-forming polymer and quinine can be coated outside the core as a layer to form a coated core.

[0067] In another embodiment, the core itself may contain quinine. The quinine-containing core may be formed into granules or spheroids (spherical particles) by granulation and spheronization methods known in the art.

[0068] The particles may be enclosed in hard gelatin capsules containing a therapeutically effective amount of the active ingredient per unit dosage form. When the quinine contained in the controlled-release particles accounts for about 60-90 wt%, specifically about 70-80 wt% of the total quinine in the dosage form, and the quinine contained in the quick-release dosage form accounts for about 10-40 wt%, specifically about 20-30 wt% of the total quinine in the dosage form, the required pharmacokinetic characteristics (fast onset, horizontal peak-valley value) can be obtained

[0069] To achieve the desired pharmacokinetic profile, the dosage form may be loaded with particles having different quinine release rates, one of which is a slow release quinine and one of which is a more rapid release quinine, particularly one which releases the active ingredient immediately, such as the particles described herein which are not coated with a release retarding material.

[0070] These different particles may be encapsulated sequentially or they may be premixed and encapsulated (taking into account possible separation situations)

[0071] In addition, the controlled-release particles may further comprise a water-soluble polymer-quinine coat (top-coat) as described above, so that the particles are released almost immediately after being swallowed, thereby ensuring a rapid onset of action.

[0072] In another embodiment, the capsule contains the controlled release particles (about 60-90 wt%, specifically about 70-80 wt% of the total quinine in the dosage form) and one or more mini-tablets (minitablets) containing the remainder of the quinine.

[0073] The quinine formulation may be coated externally with a material to delay the release of quinine until the formulation is released upon exposure to the intestinal tract. Such formulations include enteric coated formulations which are externally coated with a non-toxic composition comprising a pharmaceutically acceptable enteric polymer which is predominantly soluble in intestinal fluid and practically insoluble in gastric fluid. Enteric coatings prevent the release of the active ingredient until the dosage form reaches the small intestine. The enteric dosage form comprises quinine or a salt thereof coated with an enteric polymer, such as polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Cellulose Acetate Phthalate (CAP), methacrylic acid copolymer, hydroxypropylmethylcellulose succinate, cellulose acetate hexahydrophthalate, hydroxypropylmethylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, methacrylic acid/methacrylate polymer (acid number 300-, type a NF), methacrylic acid-methyl methacrylate copolymers, ethyl methacrylate-methyl methacrylate-trimethyl ammonium chloride ethyl methacrylate copolymers, and the like, as well as combinations comprising at least one of the foregoing enteric polymers. Other examples include natural resins such as shellac, SANDARAC, copal collophorium, and combinations comprising at least one of the foregoing polymers. Other examples of enteric polymers include synthetic resins with carboxyl groups. Also suitable are the methacrylic acid to ethyl acrylate 1: 1 copolymer solids of the acrylic dispersions sold under the trade name EUDRAGIT L-100-55.

[0074] In preparing the sustained-release quinine formulation, a portion of the immediate-release formulation may be included in the formulation. Typically, at least a portion of the dosage form will be quinine in a sustained release form, while the other portion will be an immediate release form. Immediate and sustained release dosage forms of quinine may be obtained according to different principles, for example using a single dose of layered pellets or tablets, multiple doses of layered pellets or tablets, or single or multiple doses of layered pellets or tablets containing two or more different components, optionally in combination with immediate release pellets or tablets. The multi-dose layered pellets may be filled into capsules or compressed into multi-dose tablets with tablet excipients. In addition, multi-dose layered tablets may also be prepared.

[0075] The pellets or tablets may comprise a core, optionally forming a layer on the kernel/pellet, which core comprises quinine and a water-swellable substance, with an optional immediate release layer on the outside of the core; and a fast-release type outer coating layer containing quinine. In addition, the layered pellets or tablets may also comprise: a quinine-containing core; a coating layer containing a water-swellable substance; a fast-release outer coating layer containing quinine; and an immediate release layer selected for ease of processing or to improve the stability of the dosage form.

[0076] In another embodiment, the partial quinine is present in an immediate release form, e.g., as particles without a coating of release retarding material, or as an immediate release mini-tablet, or as a coating on the surface of a sustained release formulation.

[0077] Quinine or its pharmaceutically acceptable salt formulations may also be prepared using OROS technology (Alza corporation, Mountain View, Calif.) (also known as "osmotic pumps"). Such dosage forms contain a fluid-permeable (semipermeable) membrane wall, an osmotically active expansion-driving membrane (osmotically expandable layer), and a dense portion for the delivery of the active agent. In osmotic pump dosage forms, quinine may diffuse outward through an exit device containing channels, openings, etc., under the influence of an osmotically active driving membrane. The active agent in the osmotic pump dosage form may be formulated as a heat-sensitive formulation wherein quinine is dispersed in a heat-sensitive composition. Additionally, the osmotic pump dosage form may also contain a heat-responsive moiety comprising a heat-responsive composition and a quinine composition at the interface of the osmotically expandable layer.

[0078] As used herein, the term "heat-responsive" includes thermoplastic compositions that soften or diffuse when heated and harden when cooled. The term also includes thermotropic compositions that undergo a gradient change under the influence of energy. These compositions exhibit temperature sensitivity when energy is applied or removed. Heat-sensitive compositions are generally solid or solid at temperatures below about 32 deg.C, become liquid, semi-solid, or become viscous at temperatures above about 32 deg.C, and usually between 32 and 40 deg.C. A heat-sensitive composition, including a heat-sensitive carrier, has the property of melting, dissolving, decomposing, softening, or liquefying at an elevated temperature to form a dispersible composition. The thermo-responsive vehicle may be lipophilic, hydrophilic or hydrophobic. Another property is that the stability of the formulation is maintained during storage and release of the formulation. The heat-responsive composition can be readily excreted, metabolized, or absorbed after diffusion into the biological environment.

[0079] The osmotic pump dosage form comprises a semipermeable membrane. The capsule or other dispersion of the osmotic pump dosage form may have an outer wall that includes a selectively semipermeable material. The selectively semipermeable material is not adversely affected by the host or animal, is permeable to external aqueous fluids such as water or biological fluids, and is substantially impermeable to the active agent, and remains intact, i.e., does not melt or erode, in the presence of the heat-and heat-responsive composition. The selectively semi-permeable material forming the outer wall is practically insoluble, non-toxic and non-erodible in the body fluid.

[0080] Representative materials for forming the selectively semipermeable wall include semipermeable homopolymers, semipermeable copolymers, and the like. Suitable materials include, for example, cellulose esters, cellulose monoesters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, and combinations comprising at least one of the foregoing materials. The degree of substitution (d.s.) on the anhydroglucose unit of these cellulose polymers is in the range of greater than 0 and equal to or less than 3. The degree of substitution refers to the average number of hydroxyl groups originally present on the anhydroglucose unit that are substituted or converted to other groups by substituents. The anhydroglucose units may be partially or fully substituted with a semipermeable membrane-forming group such as an acyl group, an alkanoyl group, an aroyl group, an alkyl group, an alkenyl group, an alkoxy group, a halogen, an alkylcarbonyl group, an alkyl carbamate, an alkyl carbonate, an alkyl sulfonate, an alkyl sulfamate, or the like.

[0081] Other selectively semi-permeable materials include, for example, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di-, and tri-cellulose alkylate, mono-, di-, and tri-cellulose alkenylate, mono-, di-, and tri-cellulose arylacylate, and the like, as well as combinations comprising at least one of the foregoing materials. Typical polymers including cellulose acetate have a degree of substitution of 1.8 to 2.3, and an acetyl content of about 32 to 39.9%; comprising cellulose diacetate having a degree of substitution of 1-2 and an acetyl content of about 21-35%; including cellulose triacetate having a degree of substitution of 2 to 3, an acetyl content of about 34 to 44.8%, and the like. More specific cellulosic polymers include cellulose propionate, with a degree of substitution of 1.8, a propionyl content of about 38.5%; cellulose acetate propionate having an acetyl content of about 1.5 to 7% and a propionyl content of about 39 to 42%; cellulose acetate propionate having an acetyl content of about 2.5 to 3%, a propionyl average content of about 39.2 to 45%, and a hydroxyl content of about 2.8 to 5.4%; cellulose acetate butyrate, degree of substitution 1.8, an acetyl content of about 13-15%, and a butyryl content of about 34-39%; cellulose acetate butyrate having an acetyl content of about 2 to 29.5%, a butyryl content of about 17 to 53%, and a hydroxyl content of about 0.5 to 4.7%; cellulose triacylate, with a degree of substitution of 2.9 to 3, such as cellulose pivalate, cellulose trilaurate, cellulose tripalmitate, cellulose tricaprylate, and cellulose tripropionate; cellulose diesters having a degree of substitution of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctoate, cellulose dicaryylate and the like; mixed cellulose esters such as cellulose acetate valerate, cellulose acetate succinate, cellulose propionate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptanoate, and the like, as well as combinations comprising at least one of the foregoing polymers.

[0082] Other selectively semipermeable polymers include, for example, acetaldehyde dimethylcellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, cellulose dimethylglycinate, semipermeable polyamides, semipermeable polyurethanes, semipermeable polysulfanes, semipermeable sulfonated polystyrenes, crosslinked selectively semipermeable polymers formed by co-precipitation of polyanions and polycations, selectively semipermeable silicone rubbers, semipermeable polystyrene derivatives, semipermeable poly (sodium styrene sulfonate), semipermeable poly (vinylbenzyltrimethyl) ammonium chloride polymers, and combinations comprising at least one of the foregoing polymers.

[0083] The osmotically distending driving membrane or osmotically distendable layer in an osmotic pump dosage form is an expandable and expandable inner layer. The materials used to form the osmotically expandable layer are polymeric materials alone and/or polymeric materials mixed with osmotic agents that interact with water or biological fluids to swell or expand upon absorption of the fluid to an equilibrium state. The polymer should be able to retain the majority of the absorbed fluid within the polymer molecular structure. Such polymers may be, for example, gel polymers which swell or expand to a very high degree, typically about 2 to 50 times greater in volume. The swellable hydrophilic polymers, also known as osmopolymers, may be non-crosslinked or lightly crosslinked polymers. This crosslinking means the formation of covalent or ionic bonds with polymers that swell in the fluid but are insoluble. The polymer can be extracted from plants, animals or synthesized. Polymeric materials useful for the above purposes include poly (hydroxyalkyl methacrylates) having a molecular weight of about 5,000-5,000,000, poly (vinyl pyrrolidone) having a molecular weight of about 10,000-360,000, anionic and cationic hydrogels, poly (electrolyte) composites, poly (vinyl alcohol) s containing a small amount of acetate residues, expandable mixtures containing agar and carboxymethyl cellulose, expandable compositions containing methyl cellulose mixed with lightly crosslinked agar, water swellable copolymers made from dispersions of fine particulate copolymers of maleic anhydride with styrene, ethylene, propylene or isobutylene, water swellable polymers containing N-vinyl lactam, and the like, as well as combinations comprising at least one of the foregoing polymers. Other polymers useful for forming the osmotic expandable layer that are gellable, fluid-absorbing and fluid-retaining include pectin having a molecular weight of about 30,000-300,000, agar, gum arabic, karaya gum, tragacanth gum, algin, guar gum and like polysaccharides, acidic carboxyl polymers and their salt derivatives, polyacrylamide, indene-maleic anhydride water-swellable polymers, polyacrylic acid having a molecular weight of about 80,000-200,000, POLYOX, polyethylene oxide polymers having a molecular weight of about 100,000-5,000,000 or greater, starch graft copolymers, polyanions and polycation exchange polymers, starch-polyacrylonitrile copolymers, acrylate polymers having a water absorption capacity of up to about 400 times their initial weight, polydextrose-diester cross-linked polyvinyl alcohol and poly (N-vinyl-2-pyrrolidone), zein, which can be used as an prolamine, Polyethylene glycol having a molecular weight of about 4,000-100,000, and the like, as well as combinations comprising at least one of the foregoing polymers.

[0084] The osmotic expansion driving layer of an osmotic pump dosage form may further contain an osmotic compound (osmotic agent) either neat or intimately or non-homogeneously mixed with the expandable polymer, which may be used to form the layer. Such osmotic agents include osmotic solutes that are soluble in the fluid absorbed by the swellable polymer and that form an osmotic pressure gradient from the semipermeable wall to the external fluid. Suitable osmotic agents include, for example, solid compounds such as magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose, and the like, as well as combinations comprising at least one of the foregoing osmotic agents. The osmotic pressure of the osmotic agent may be greater than about 0atm, typically from about 0 to about 500atm, or higher.

[0085] The swellable, expandable polymer in the osmotically expandable drive layer may also serve as a supporting matrix for the osmotic compound, in addition to providing a driving source for the release of the active agent from the dosage form. The permeating compound may be homogeneously or non-homogeneously mixed with the polymer to provide the desired expanded wall or bag. In the preferred embodiment, the composition comprises (a) a polymer and a permeating compound, or (b) a solid permeating compound. Generally, the composition will comprise from about 20 to about 90 weight percent of the polymer and from about 10 to about 80 weight percent of the osmotically active compound, with the preferred composition in this instance comprising from about 35 to about 75 weight percent of the polymer and from about 25 to about 65 weight percent of the osmoactive compound, based on the total weight of the composition.

[0086] The quinine in an osmotic pump dosage form may be formulated as a heat-sensitive formulation, wherein the quinine is dispersed in a heat-sensitive composition. Alternatively, the osmotic pump formulation may contain a heat-responsive moiety comprising the quinine composition and the heat-responsive composition at the interface of the osmotically distended layer. Representative heat-sensitive compositions and their melting points are as follows: cocoa butter (32 ℃ -34 ℃), cocoa butter plus beeswax (35 ℃ -37 ℃), mono-and distearates of propylene glycol (32 ℃ -35 ℃), hydrogenated oils such as hydrogenated vegetable oil (36 ℃ -37.5 ℃), 80% hydrogenated vegetable oil and 20% sorbitan monopalmitate (39 ℃ -39.5 ℃), 80% hydrogenated vegetable oil and 20% polysorbate 60(36 ℃ -37 ℃), 77.5% hydrogenated vegetable oil, 20% sorbitan trioleate, 2.5% beeswax and 5.0% distilled water (37 ℃ -38 ℃), mono-, di-and triglycerides with 8-22 carbon atoms of saturated and unsaturated acids including palmitic, stearic, oleic, linoleic, linolenic and arachidonic acids; fatty acid triglycerides containing mono-and diglycerides (34 ℃ -35.5 ℃) propylene glycol monostearate and propylene glycol distearate (33 ℃ -34 ℃), partially hydrogenated cottonseed oil (35 ℃ -39 ℃), a block polymer of polyalkylene oxide and propylene glycol; a block polymer containing 1, 2-butylene oxide to which ethylene oxide is added; a block copolymer of propylene oxide and ethylene oxide, hardened fatty alcohol and fat (33 ℃ to 36 ℃), 1, 5-hexadiene alcohol and hydrated lanolin triethanolamine monostearate glyceride (38 ℃), a low eutectic mixture of monoglycerides, diglycerides and triglycerides (35 ℃ to 39 ℃), WITEPSOL #15, saturated vegetable fatty acid triglycerides containing monoglycerides (33.5 ℃ to 35.5 ℃), WITEPSOLH32(31 ℃ to 33 ℃), a saponification number of 225-, 47% polyethylene glycol 6000 and 20% distilled water (39 ℃ -41 ℃), 30% polyethylene glycol 1500, 40% polyethylene glycol 4000 and 30% polyethylene glycol 400(33 ℃ -38 ℃), a mixture of monoglycerides, diglycerides and triglycerides of saturated fatty acids containing 11-17 carbon atoms (33 ℃ -35 ℃), and the like. These heat-sensitive compositions, including a heat-sensitive carrier, are used to preserve the active agent contained in the solid composition at a temperature of about 20 ℃ to 33 ℃, maintain immiscible boundaries (immiscibility) at the expandable composition interface, and disperse the active agent in the flowable composition at a temperature greater than about 33 ℃, particularly at a temperature of 33 ℃ to 40 ℃.

[0087] The amount of quinine contained in the osmotic pump dosage form is about 10mg-2g, or more. The osmotic dosage form may be formulated for 1 or less administration per day.

[0088] Quinine in osmotic pump dosage forms can be prepared according to a number of techniques known in the art for preparing solid and liquid oral dosage forms. The quinine can be prepared by a wet granulation technique. In a typical wet granulation process, quinine and the quinine-containing layer ingredients are mixed using an organic solvent such as isopropanol-dichloroethane 80: 20 v: v (volume ratio) as the granulation fluid. Other granulation fluids such as 100% modified ethanol may also be used. First, the quinine layer-forming ingredients are each sieved, e.g., 40 mesh, and then thoroughly mixed in a mixer. Thereafter, the other ingredients comprising the active agent layer are dissolved in a portion of the granulation fluid, such as the co-solvent described above. The wet mixture prepared later was slowly added to the previous active agent mixture and mixing continued in the mixer. The granulation fluid is added until a wet mixture is obtained, then external force is applied, the wet mixture is passed through, for example, a 20 mesh sieve onto an oven tray, dried at about 30-50 ℃ for about 18-24 hours, and then screened to size dry granules using, for example, a 20 mesh sieve. Next, the lubricant is passed through, for example, an 80-mesh sieve, and then added to the screened dry granulation mixture. These granulates are placed in a mill pot and mixed on a pot mill for about 1-15 minutes. The composition was pressed into individual layers in a KILIAN lamination press.

[0089] Another manufacturing process that can be used to produce the quinine layer and the osmotically-expansive driving layer involves the step of separately producing each layer by mixing powdered ingredients in a fluid bed granulator. After dry mixing the powdered ingredients in a granulator, a granulating fluid, such as poly (vinyl-pyrrolidone) dissolved in water, modified ethanol, 95: 5 ethanol/water or a mixture of ethanol and water, is sprayed onto the powders. In some cases, the above components may be dissolved or suspended in the granulating fluid. The coated powder was then dried in a granulator. This method is to form the ingredients therein into granules upon addition of a granulating fluid. After the obtained granules are dried, a lubricant such as stearic acid or magnesium stearate is added into the granulator. The particles are then pressed into individual layers in the manner described above.

[0090] The quinine formulation and the osmotically expandable layer in an osmotic dosage form may also be manufactured by mixing quinine with the ingredients forming the composition and compressing the composition into a solid sheet of a size consistent with the internal diameter of the cavity in which it is located. In another manufacturing process, quinine, other quinine-composition-forming ingredients and solvents are mixed into a solid or semi-solid by ball milling, calendaring, stirring or roller milling, and then pressed into the shape of a preselected layer. A layer of the composition containing the osmopolymer and optional osmotic agent is then contacted with the quinine-containing layer above. The above quinine-containing first layer may be laminated with a second layer of a composition containing an osmopolymer and optionally an osmotic agent using conventional lamination techniques. The semipermeable wall-forming material can be wrapped on the exterior of the pressed double-layer form by molding, spraying, and immersing to obtain the semipermeable wall. An air suspension coating process may also be used to form the semipermeable wall of the osmotic dosage form, which process comprises suspending the bilayer in an air stream and tumbling until the semipermeable wall-forming material encases the layer.

[0091] The dispersion of the osmotic pump dosage form may be in the form of a capsule. The capsule may comprise an osmotic hard capsule and/or an osmotic soft capsule. The osmotic hard capsules may be composed of two parts: a cap and a body which are assembled together by sliding or telescoping the cap portion over the body portion after the larger body is filled with the active agent so that the active agent is completely enclosed within the capsule. Hard capsules can be prepared using techniques known in the art.

[0092] The osmotic pump dosage form of the soft capsule may be a one-piece osmotic soft capsule. Generally, osmotic soft capsules are sealed structures that encapsulate an active agent. The soft capsule can be produced by various methods such as plate method, rotary die method, reciprocating die method and connecting method.

[0093] Materials used to form osmotic pump dosage form capsules are commercially available materials including gelatin, gelatin having a viscosity of about 5 to 30 millipoise and bloom strength (bloom strength) of up to about 150 grams; gelatin with bloom strength of about 160-; a composition comprising gelatin, glycerol, water and titanium dioxide; a composition comprising gelatin, erythrosine, iron oxide and titanium dioxide; a composition comprising gelatin, glycerin, sorbitol, potassium sorbate, and titanium dioxide; compositions comprising gelatin, gum arabic, glycerin, and water, and the like, as well as combinations comprising at least one of the foregoing materials.

[0094] The semipermeable wall-forming composition can be applied to the outer surface of the layered capsule by molding, shaping, air spraying, dipping or brushing. Other techniques for coating semipermeable walls that may be used are air suspension and plate coating. The air suspension process involves suspending the above capsules in an air stream and a semipermeable wall-forming composition, which is continuously tumbled until the semipermeable wall-forming material coats the capsules. The process can be repeated using different semipermeable wall-forming compositions to form a semipermeable laminar wall.

[0095] Typical solvents suitable for making semipermeable walls include inert inorganic and organic solvents that do not adversely affect the material, capsule wall, active agent, heat-sensitive composition, expanded film, or final dispersion. The solvent used to make the semipermeable wall can be an aqueous solvent, an alcohol, a ketone, an ester, an ether, an aliphatic hydrocarbon, a halogenated solvent, a cycloaliphatic, an aromatic hydrocarbon, a heterocyclic solvent, and combinations comprising at least one of the foregoing solvents. Specific solvents include acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene chloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, diethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1, 4-dioxane, tetrahydrofuran, water, and mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethanol, methylene chloride and methanol, ethylene dichloride and methanol, and combinations comprising at least one of the foregoing solvents. The semipermeable wall may be coated at a temperature a few degrees below the melting point of the thermally-responsive composition. Alternatively, the heat-responsive composition may be added to the dispersion after coating the semipermeable wall.

[0096] The exit means or orifice for release of the active agent in the osmotic pump dosage form may be formed by mechanical or laser drilling, or by ablation of an erodible portion of the wall. The opening may be a polymer inserted into the semipermeable wall, the polymer being a porous polymer having pores, or a microporous polymer having micropores.

[0097] Other sustained-release preparations may include preparations that facilitate administration to patients who have difficulty taking oral solid preparations such as tablets and capsules. Such formulations are suitable for use by children and elderly patients who require agents that are easily swallowed. Therefore, formulations such as chewable tablets, jellies, confections, sprays, liquids (such as suspensions or emulsions), taste-masking agents, and fast-dissolving tablets that are easy to administer are desirable.

[0098] A sustained release dosage form that is easy to administer can be a chewable tablet containing quinine or a salt thereof. The chewable tablet comprises a chewing base and optionally a sweetener. The chewing base comprises an excipient, such as mannitol, sorbitol, lactose, or a combination comprising at least one of the foregoing excipients.

[0099] The chewable dosage form may additionally contain preservatives, agents to prevent sticking to the oral cavity and crystalline sugars, flavoring agents, acidulants, coloring agents, and combinations comprising at least one of the foregoing agents. Glycerol, lecithin, hydrogenated palm oil or glyceryl monostearate can be used as crystal sugar protectant at a content of about 0.04-10% of the total weight of the composition to prevent the product from sticking in the oral cavity and improve its softness. Additionally, isomalt (isomalt) or liquid maltitol may be used to enhance the chewiness of the chewable dosage form.

[0100] Because quinine has a bitter taste, the quinine can be treated with taste masking treatment for better patient compliance. Quinine may be placed in microparticles, where each microparticle has quinine or a salt thereof and a protective material added. The microparticles may be in the form of microcapsules or matrix-like microparticles. The microcapsules may be loaded with a plurality of discrete quinines or salts thereof coated with discrete, individually observable coatings of protective materials. Some microparticles may combine the properties of microcapsules and matrix-like particles. For example, the microparticles may include a core comprising a dispersion of quinine or a salt thereof within a first protective material and a coating comprising a second protective material, which may be the same or different from the first protective material coating the core. Alternatively, the microparticles may also include a core consisting essentially of quinine or a salt thereof and a coating containing a protective material, the coating itself containing some quinine or a salt thereof dispersed therein. In particular, the protective material may be a release retarding material and/or a taste masking material.

[0101] The average outer diameter of the microparticles may be up to about 600 μm, specifically about 75-500 μm, more specifically about 150-500 μm. Microparticles of about 200 μm or more may be used. Thus, the microparticles may be of U.S. standard size between about 200-30 mesh, specifically about 100-35 mesh.

[0102] Sprays include particulate or pellet quinines or salts thereof, which may have a functional or non-functional coating, and the patient or caregiver may spray the particles/pellets into a drink or onto soft food. Sprays can contain particles with a major dimension of about 10-100 μm. The spray may be an optionally coated granule or microcapsule. In particular, sprays are slow release formulations. See U.S. patent No.5,084,278, which is incorporated herein by reference for its teachings in that the microcapsule formulations can be administered as a spray.

[0103] Another oral dosage form is a non-chewable fast dissolving agent of quinine. These dosage forms can be prepared by methods known to those of ordinary skill in the art of pharmaceutical formulation. For example, Cima Labs laboratories manufactured an oral dosage form comprising microparticles and effervescent agents that dissolve rapidly in the mouth and mask the bitter taste sufficiently, and manufactured a rapid dissolve dosage form comprising an active agent and a matrix comprising an indirect compression filler and a lubricant. Teachings on the fast-dissolving dosage form are given in U.S. Pat. No.5,178,878 and U.S. Pat. No. 6,221,392.

[0104] Typical fast-dissolving dosage forms include mixtures of water and/or saliva-activated effervescent disintegrants with microparticles. The microparticles may include those described above for use as chewable dosage forms. The mixture comprising the microparticles and effervescent disintegrant may be in the form of a tablet of a size and shape suitable for direct oral administration to a patient. The tablet disintegrates almost completely upon exposure to water and/or saliva. The effervescent disintegrant comprises an effective amount to aid disintegration of the tablet in the mouth of a patient, resulting in a noticeable effervescent sensation.

[0105] Bubbling not only is pleasant for the patient, but it also tends to stimulate salivation, thereby gaining more moisture and helping to produce more bubbles. Therefore, the tablet disintegrates almost completely and rapidly as soon as it is placed in the mouth of a patient, without any active action by the patient. The tablet disintegrates rapidly, although not chewed by the patient. Upon disintegration of the tablet, the microparticles are released and become a slurry or dispersion of microparticles which are then swallowed. The microparticles are then transferred into the patient's stomach and then broken down in the digestive tract, with the drug substance being distributed systemically.

[0106] "effervescent disintegrant" includes gas-generating compounds. An effervescent tablet desirably undergoes a chemical reaction to produce a gas upon the effervescent disintegrant encountering water and/or saliva in the oral cavity. This bubbling reaction is mostly the result of the reaction of a soluble source of acid with an alkali metal carbonate or carbonate source. The two compounds react with water in saliva to generate carbon dioxide gas.

[0107] Such water-activated materials can be stored in a substantially water-free, moisture-free condition or stable hydrated form because they prematurely disintegrate the tablet upon contact with water. An acid source or acid that is safe for human ingestion may be used, and generally includes edible acids, anhydrides, and acid salts. The edible acid includes citric acid, tartaric acid, malic acid, fumaric acid, fatty acid, succinic acid, etc. Because of the direct swallow, the overall water solubility of these acids is not as important as is required to dissolve an effervescent tablet in a water cup. Anhydrides of the above acids may also be used. Acid salts may include sodium dihydrogen phosphate, acid citrate, and sodium bisulfite.

[0108] Ketoacid salt sources include dry carbonate and bicarbonate solids, such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycinate carbonate, L-lysine carbonate, arginine carbonate, amorphous calcium carbonate, and combinations comprising at least one of the foregoing carbonates.

[0109] Effervescent disintegrants do not react completely to form carbon dioxide. It is also contemplated to use reactants that generate oxygen or other safe gases. When the effervescent agent comprises two mutually reactive components, such as an acid source and a carbonate source, it is preferred that the two components react almost completely. Therefore, the equivalent ratio (equivalent ratio) of the composition for obtaining the same equivalent amount is preferred. For example, if a dibasic acid is used, the acid should be completely neutralized using 2 times the amount of the monobasic reaction carbonate base or the same amount of the dibasic reaction base. However, the amount of acid or carbonate source may be greater than the amount of the other component, which may help to enhance the taste and/or performance of a tablet containing an excess of either component. In this case, it is also possible that the reaction of any one of the components in such an excess is incomplete.

[0110] In general, effervescent disintegrants are used in tablets in amounts of from about 5 to about 50 wt%, specifically from about 15 to about 30 wt%, and more specifically from about 20 to about 25 wt% of the final composition.

[0111] Other fast dissolving quinine dosage forms may be prepared without effervescent agents using spray dried hydrocarbon or sugar alcohol excipients (e.g., sorbitol, mannitol, combinations comprising at least one of the foregoing, and the like), optionally in combination with a disintegrant (e.g., a disintegrant selected from crospovidone, croscarmellose, sodium starch glycolate, combinations comprising at least one of the foregoing, and the like), and/or a flow agent (e.g., a silica sol, a silica gel, a white carbon, combinations comprising at least one of the foregoing, and the like). Suitable fast dissolving agents can be found in published U.S. patent application No. US20030118642A1 to Norman et al, which is incorporated herein in its entirety.

[0112] The instant tablets should disintegrate rapidly after oral administration. The term "rapid" is understood to mean that the tablet disintegrates in the mouth of a patient within about 10 minutes, preferably within about 30 seconds to about 7 minutes, and in particular that the tablet dissolves within about 30 seconds to about 5 minutes. The oral disintegration time can be determined by observing the disintegration time of the tablet in water at about 37 ℃. The tablets were immersed in water without stirring. The time from the immersion of the tablet until the tablet is almost completely dispersed is the disintegration time by visual observation. Herein, a tablet "fully disintegrates" does not require the disintegration or disintegration of microparticles or other discrete contents.

[0113] The fast dissolving tablets may be manufactured by known tablet manufacturing methods. In a conventional tablet manufacturing process, the material to be tableted is first placed in a cavity, and then one or more punch members are inserted into the cavity, brought into intimate contact with the material to be compressed, and pressure is applied. The tablet material is thus compressed into a shape conforming to the die and cavity. This mode of production can produce hundreds or even thousands of tablets per minute.

[0114] Because quinine has a particular bitter taste, it is desirable to produce a solid taste-masking form of quinine. The solid taste-masking agent comprises a core portion containing quinine or a salt thereof and a coating covering the core portion. The core portion containing quinine or a salt thereof may be in the form of a capsule, or encapsulated by microencapsulation techniques wherein a polymeric coating is applied over the formulation. The core portion may also include excipients, fillers, flavoring agents, stabilizers, and/or coloring agents.

[0115] In taste masked dosage forms, the core member comprising quinine or a salt thereof may comprise from about 77 to about 100 wt%, and in particular from about 80 to about 90 wt%, of the total weight of the composition, and the substantially continuous coating formed on the surface of the core member by a coating material comprising a polymer may comprise from about 20 to about 70 wt%. The core element comprises about 52-85 wt% quinine or a salt thereof and about 5-25 wt% additional components selected from the group consisting of waxes, water-insoluble polymers, enteric polymers and partially water-soluble polymers, other suitable pharmaceutical excipients, and combinations comprising at least one of the foregoing.

[0116] The coating material of the taste-masked preparations described above can be in a form which results in both an almost continuous coating and also a taste-masking effect. In some cases, the coating also serves to control the release of the active agent. The polymer used for the taste-masking type coating may be a water-insoluble polymer, such as ethyl cellulose. The coating material may further comprise a plasticizer.

[0117] The process for preparing masked pharmaceutical preparations such as powder preparations comprises: the core portion and the coating material are mixed in a diluent and the mixture is spray dried to form the taste masked formulation. The process for drying the active agent and polymer in the solvent includes spraying a stream of air into the atomized dispersion to evaporate the solvent and leave the active agent coated with the polymer coating material.

[0118] It is possible to prepare a liquid dosage form of quinine or a salt thereof, which is sufficiently taste-masked and has sustained-release properties. Taste masked liquid dosage forms may comprise suspensions of taste masked particles (e.g., microparticles). The coating of the active agent particles with a polymeric material inhibits or delays the rate of dissolution and dissolution of the active agent, which overcomes the taste problems associated with the release of the active agent from suspension. This polymer coating allows time for all particles to be swallowed before the threshold concentration in the mouth is reached.

[0119] Taste masked liquid dosage forms comprise an active agent, a polymer encapsulating the active agent, and a suspension medium suspending the encapsulated active agent. The polymer or polymers and suspension medium act as a taste masking effect on the active agent.

[0120] The quinine may be in its neutral or salt form, and may be in the form of particles, crystals, granules, microparticles, powders, pellets, amorphous solids, or precipitates. These particles may further comprise other functional components. The quinine particles may have a defined particle size distribution, specifically, less than or equal to about 100 μm, more specifically, less than or equal to about 750 μm, more specifically, less than or equal to about 500 μm, yet more specifically, less than or equal to about 250 μm, and yet more specifically, less than or equal to about 150 μm, within which the mouthfeel is acceptable without chewing residual particles and releasing the active agent to taste.

[0121] Taste masked liquid dosage forms may include quinine or a salt thereof, as well as other functional components for altering the physicochemical or taste properties of quinine. For example, the quinine may be an ion-exchange or cyclodextrin complex, or the quinine may be combined with various additives, such as waxes, lipids, disintegration inhibitors, taste-masking or odor-suppressing agents, carriers or excipients, fillers, and combinations comprising at least one of the foregoing, to form a mixture or dispersion. In such taste masked formulations, the quinine salt particles may be of any size from the molecular level to about micron size.

[0122] The pharmaceutically active agent or active agent particles may be suspended, dispersed or emulsified in the suspending medium after encapsulation with the polymer. The suspending medium may be an aqueous based medium but may also be a non-aqueous carrier. The taste masked liquid dosage forms may further include other optional solubilizing or suspending agents to stabilize the suspension. They include suspending or stabilizing agents such as methylcellulose, sodium alginate, xanthan gum, polyvinyl alcohol, microcrystalline cellulose, silica sol, bentonite, and combinations comprising at least one of the foregoing. Other materials used include preservatives such as methyl benzoate, ethyl benzoate, propyl benzoate, and butyl benzoate, sweetening agents such as sucrose, sodium saccharin, aspartame, mannitol, flavoring agents such as grape, cherry, peppermint, menthol, and vanilla, antioxidants, or other stabilizers, and combinations comprising at least one of the foregoing.

[0123] Encapsulation of microparticles or active agent particles with polymers may be accomplished by methods such as suspending, dissolving or dispersing the particles in a solution or dispersion of a polymeric coating material, spray drying, fluid bed coating, mono-or complex coacervation, co-evaporation, co-milling, melt dispersion and emulsion-solvent evaporation techniques, and the like.

[0124] Alternatively, polymer-coated quinine or salt powders may be used to prepare reconstitutable powders, i.e. dry powdered active agent drugs, which may be reconstituted to a suspension or emulsion by the addition of a liquid medium, such as water, prior to use. The reconstitutable powder has a long shelf life and the resulting suspension after reconstitution can fully mask the bitter taste.

[0125] Suitable liquid taste-masking agents include those described in U.S. patent 6,197,348.

[0126] Quinine or its pharmaceutically acceptable salt can also be made into long acting parenteral preparation (depotformulation). The parenteral depot formulation is injected or implanted into muscle or subcutaneous tissue to release quinine in a controlled release manner. The advantage of a long acting dosage form is that the quinine sustained release can last for up to several days or weeks.

[0127] Such formulations may be in the form of microparticles or implants (e.g. rods). The implant is a rod-like device that is injected into the subcutaneous tissue with a large bore needle. The microparticles are generally spherical in shape, and generally have a size of about 1 to 1000. mu.m, specifically about 10 to 100. mu.m, and can be injected intramuscularly or subcutaneously. The microparticles may include (1) microcapsules that form a solid dispersion or solid solution (solid solution), quinine-containing microparticles within a core coated with a polymeric film, and (2) microspheres, microparticles containing a drug in a polymeric matrix.

[0128] The depot can be prepared with biodegradable polymeric excipients or non-biodegradable polymeric excipients. The polymeric excipient controls the rate of drug release and, in the case of biodegradable materials, is absorbed during and/or after drug release.

[0129] A typical biodegradable polymer is a lactide/glycolide polymer, while a typical non-biodegradable polymer is ethylene-vinyl acetate copolymer. By varying the composition of the polymer composition, the overall drug release can be controlled. For example, increasing the lactic acid level in the lactide/glycolide polymer delays drug release, increasing the polymer molecular weight also delays drug release and prolongs in vivo efficacy.

[0130] Typical sustained release forms are shown in U.S. patent 5,102,666, which is incorporated herein by reference. The patent describes a polymeric composition comprising a reaction complex formed by reacting (1) a calcium polycarbophil component, a water-swellable, water-insoluble fiber cross-linked carboxyl-functional polymer comprising (a) a plurality of repeating units at least about 80% of which contain carboxyl functionality, and (b) from about 0.05 to about 1.5% of a cross-linking agent substantially free of a polyalkenyl polyether, the percentages being based on the weight of unpolymerized repeating units and the weight of the cross-linking agent, respectively, with (2) water in the presence of an activating agent.

[0131] The calcium polycarbophil may be present in an amount of about 0.1 to about 99 wt%, for example about 10%. The quinine or salt thereof may be present in an amount of from about 0.0001 to about 65 wt%, for example from about 5 to about 20 wt%, of the reaction complex. The water content may be about 5 to 200 wt%, for example about 5 to 10 wt%. The reaction is carried out at a pH of about 3 to 10, for example about 6 to 7. Calcium polycarbophil is initially present as a calcium salt containing about 5-25 calcium.

[0132] There are several types of materials that are suitable for forming the components of the calcium polycarbophil composition. The polymer comprises a plurality of repeating units at least about 80% of which contain carboxyl functionality and about 0.05-1.5% of a crosslinking agent that is substantially free of polyalkenyl polyether, the percentages being based on the weight of unpolymerized repeating units and crosslinking agent, respectively. Specifically, at least about 90% of the repeat units contain carboxyl functionality; more specifically, at least about 95% contain carboxyl functionality; more specifically, the material is the reaction product of only one carboxyl-functional monomer and a crosslinking agent. More specifically, the component contains about 0.1 to 1 weight percent of a polymeric crosslinker. The material also contains 5-25%, specifically 18-22% calcium as the calcium salt of the polymer salt, some of which are commercially available under the generic name "calcium polycarbophil".

[0133] The calcium polycarbophil-type composition used herein is therefore at least 80% by weight of the carboxyl functional monomer in a monoethylenically unsaturated form and about 0.05 to 1.5% by weight of the crosslinking agent free of the polyalkenyl polyether, and 18 to 22% calcium.

[0134]In addition to the above two components, polyThe carbomer-type polymer may also include polymerized monoethylenically unsaturated repeat units such as C of the above acids₁-C₆Alkyl esters such as hexyl acrylate, butyl methacrylate, and methyl crotonate; hydroxyalkylene-functional esters of the above acids containing on average 1 to about 4 oxyalkylene groups containing 2 to 3 carbon atoms per molecule, e.g. hydroxyethyl methacrylate, hydroxypropyl acrylate and tetraethylene glycol monoacrylate, amides of methacrylic acid, amides of acrylic acid and C thereof₁-C₄Monoalkyl and dialkyl derivatives such as N-methacrylamide, N-butyl methacrylamide and N, N-dimethylacrylamide; styrene, and the like, which are known in the art to form copolymers with the above carboxyl functional group-containing monomers and crosslinking agents. Most particularly, the polymer is prepared from only the monoethylenically unsaturated form of the carboxy-functional monomer and the crosslinking agent.

[0135] The calcium polycarbophil reacts with water to form a composite hydrogel matrix structure, and then internal quinine or a salt thereof is controlled to diffuse or otherwise be transported out of the matrix. The level of controlled or sustained release will vary depending on the ratio of the components used, the physical state of the quinine or salt thereof, the method of mixing, the order of mixing the components, and the like. Other additives may also be added to modify the matrix characteristics and its release characteristics.

[0136] In one embodiment, a sustained release formulation comprises a polymeric composition comprising a reactive complex formed by the interaction of water and a calcium polycarbophil component, wherein the calcium polycarbophil component is a water-swellable, water-insoluble, fiber-crosslinked carboxy-functional polymer comprising (a) a plurality of repeating units, at least about 80% of which contain carboxy functional groups, and (b) from about 0.05 to about 1.5% of a crosslinking agent that is substantially free of polyalkenyl polyether, based on the weight of unpolymerized repeating units and the weight of the crosslinking agent, respectively, and the complex is formed in the presence of quinine or a pharmaceutically acceptable salt thereof.

[0137] In another embodiment, a method of making a sustained release formulation comprises: allowing water and calcium polycarbophil component to act in the presence of quinine or a pharmaceutically acceptable salt thereof; wherein the calcium polycarbophil component is a water-swellable, water-insoluble, fiber-crosslinked carboxy-functional polymer comprising (a) a plurality of repeating units at least about 80% of which contain carboxy functional groups, and (b) from about 0.05% to about 1.5% of a crosslinking agent that is substantially free of polyalkenyl polyether, the percentages being based on the weight of unpolymerized repeating units and the weight of the crosslinking agent, respectively.

[0138] Other exemplary sustained release dosage forms are described in U.S. Pat. No.5,422,123, which is incorporated herein by reference. The tablet described in this patent consists of a core of defined geometry containing the active substance, a polymer which swells in the presence of a water-based liquid, a substance with gelling properties, and possibly other substances with adjuvant functions, and a support layer covering the core partially on its surface, characterized in that the support layer consists of a polymer which slowly dissolves and/or slowly gels in the presence of a water-based liquid, a plasticizer and possibly other substances with adjuvant functions, the plasticizing action of which can also be performed by the polymer.

[0139]Can be about 1000-4000kg/cm²Compressing a core mixture containing quinine or a salt thereof under pressure into a core having a defined geometric form. Typical shapes include a cylindrical sheet with a flat, convex or concave base surface (base).

[0140] Suitable polymeric materials for the core are water-swellable polymers, such as croscarmellose sodium, croshydroxypropyl cellulose, high molecular weight hydroxypropyl methylcellulose, carboxymethyl starch, potassium methacrylate/divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone, high molecular weight polyvinyl alcohol, and the like, which are substantially insoluble. The gel polymer material comprises methylcellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight polyvinyl alcohol, polyethylene glycol, and non-crosslinked polyvinylpyrrolidone. Polymers having both swelling and gelling properties, such as medium viscosity hydroxypropyl methylcellulose and medium viscosity polyvinyl alcohol, may also be used. The adjuvant materials include mannitol, ethyl cellulose, magnesium stearate, silica sol, etc.

[0141] The ratio of expandable polymer to gelling polymer is from about 1: 9 to about 9: 1. The active agent content in the core may be from about 1 to about 95 weight percent of the total weight of the core.

[0142] The support layer is typically about 10 μm to 4mm thick, depending on the hydrophilicity of the components, and serves to limit and orient the release of the active substance from the core. Since the support layer is generally less hydrophilic than the core and does not contain an active agent, the active agent can migrate substantially immediately outward from the portion of the core not coated with the support layer.

[0143] Suitable materials which can be used for the preparation of the support layer include support polymers which dissolve slowly and/or gel slowly in aqueous liquids, either alone or in admixture with one another, selected from the group consisting of hydroxypropylmethyl cellulose having a molecular weight of about 4,000-2,000,000, high molecular weight carboxyvinyl polymers, polyvinyl alcohol, scleroglucan, acrylates, methacrylates, hydroxypropylcellulose, sodium carboxymethylcellulose and hydrophilic cellulose derivatives.

[0144] The polymer content of the support layer is about 2 to about 95 wt%, specifically about 30 to about 90 wt%, of the support layer composition. The support layer composition also includes materials that provide elasticity, such as polyethylene glycol, castor oil, hydrogenated castor oil, ethyl titanate, butyl titanate, and natural, synthetic, and semi-synthetic glycerides, and the like. The elastic support layer ensures proper release kinetics because the support layer is sufficiently elastic to follow the change in the core upon hydration without cracking or splitting which would result in premature release of the active agent throughout.

[0145] The support layer elastomers may comprise from about 0 to about 50 weight percent, specifically from about 2 to about 25 weight percent, of the total weight of the support layer.

0146] finally, the support layer composition may include binders such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic, alginic acid and its derivatives; hydrophilic agents such as mannitol, lactose, starch, silica sol; and hydrophobing agents such as hydrogenated castor oil, magnesium stearate, fatty substances, waxes, and natural and synthetic glycerides. Hydrophilic and hydrophobic agents are selected to control the hydrophilicity and desired release rate of the support layer. The binder, hydrophilic agent and hydrophobic agent may be present in an amount of about 0 to about 50 wt%, specifically about 0.5 to about 35 wt%, based on the total weight of the support layer.

[0147]The preparation steps of the support layer component are as follows: mixing, possibly wetting with binding solutions of known art, and then leaving the mixture in dry particulate form. The mixture may be sieved and then mixed with the other components to give a flowable homogeneous mixture. The prepared support layer mixture is coated on the core and pressed into the surface layer. The support layer may be coated on one or both base surfaces of the core, or on the entire surface of the core except for one base surface, or on the entire side except for both base surfaces. The support layer is typically at about 1000-²The pressure of (3) is pressed.

[0148] In one embodiment, a sustained release formulation comprises (a) a deposition core (cavity-core) having a defined geometry comprising a therapeutically effective amount of quinine or a pharmaceutically acceptable salt thereof, and a core polymeric material selected from the group consisting of (1) a swellable polymeric material and a gelling polymeric material that swell in water or an aqueous liquid, wherein the ratio of swellable polymeric material to gelling polymeric material is from about 1: 9 to about 9: 1, and (2) a polymeric material that has both swelling and gelling properties; and (b) coating the core, wherein the support platform is an elastic support layer coated on the core, the elastic support layer covers part of the surface of the core, can be changed along with the core when the core is hydrated, and can be slowly dissolved and/or slowly gelled in the aqueous liquid.

[0149] The support platform in this embodiment may comprise a polymer and a plasticizing substance that slowly dissolves and/or slowly gels in the aqueous liquid. The plasticizing substance contained in the support platform may be selected from the group consisting of polyoxyethylene glycol, castor oil, hydrogenated castor oil, ethyl titanate, butyl titanate, natural glycerides, synthetic glycerides and semi-synthetic glycerides, in an amount of about 2-15 wt% based on the total weight of the support platform.

[0150] In addition, in this embodiment, the support platform may further comprise a binder selected from the group consisting of polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic and alginic acid. The support platform may comprise a hydrophilic agent selected from mannitol, lactose, starch and silica sol. The support platform may comprise a hydrophobic agent selected from the group consisting of hydrogenated castor oil, magnesium stearate, fatty substances, waxes, natural glycerides and synthetic glycerides.

[0151] In this embodiment, the core polymeric material may be selected from the group consisting of croscarmellose sodium, cross-linked hydroxypropyl cellulose, high molecular weight hydroxypropyl methylcellulose, carboxymethyl starch, potassium methacrylate/divinylbenzene copolymer, polymethyl methacrylate, cross-linked polyvinylpyrrolidone, high molecular weight polyvinyl alcohol, methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight polyvinyl alcohol, polyethylene glycol, non-cross-linked polyvinylpyrrolidone, medium viscosity hydroxypropyl methylcellulose, and medium viscosity polyvinyl alcohol, and combinations comprising at least one of the foregoing.

[0152] In another embodiment, a method of making a sustained release formulation comprises: granulating a core-depositing component to form a core-particle mixture, wherein said core-depositing component comprises a therapeutically effective amount of quinine or a pharmaceutically acceptable salt thereof, and a core polymeric material selected from the group consisting of (1) swellable polymeric materials and gel-forming polymeric materials that swell with water or an aqueous liquid, wherein the ratio of swellable polymeric materials to gel-forming polymeric materials is from about 1: 9 to about 9: 1, and (2) a polymeric material that has both swelling and gelling properties; pressing the core particle mixture into a deposition core having a defined geometry; sieving and mixing support platform components to obtain a support layer particle mixture, wherein the support platform components comprise a polymer capable of slowly dissolving and/or slowly gelling in an aqueous liquid and a plasticizing substance; and coating the support layer particle mixture on part of the surface of the deposition core, and pressing to form a support platform covering the part of the surface of the deposition core with a certain geometric shape.

[0153] As used herein, "pharmaceutically acceptable excipient" refers to any other component of a pharmaceutical formulation other than the active agent. The excipient is added, so that the preparation is convenient, the stability is improved, the release is controlled, the product characteristic is enhanced, the bioavailability is improved, the patient acceptance is improved, and the like. Pharmaceutically acceptable excipients include carriers, fillers, binders, disintegrants, lubricants, flowing agents, compression aids, colorants, sweeteners, preservatives, suspending agents, dispersants, film formers, flavoring agents, inks, and the like.

[0154] The binder holds the formulation components together. Typical binders include, for example, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl cellulose, sugars, and combinations comprising at least one of the foregoing binders.

[0155] When the tablet is wet cracked, the disintegrant expands. Typical disintegrants include water swellable substances, for example, low substituted hydroxypropyl cellulose such as L-HPC; crosslinked polyvinylpyrrolidones (PVP-XL) such as Kollidon ® CL and Polyplasdone ® XL; croscarmellose sodium such as Ac-di-sol ®, Primellose ®; sodium starch glycolate such as Explotab ®; ion exchange resins such as Dowex ® or Amberlite ®; microcrystalline cellulose such as Avicel ®; starches and pregelatinized starches such as Starch 1500 ®; formalin-casein, and combinations comprising at least one of the foregoing water swellable agents.

[0156] Lubricants, for example, assist in the processing of powdered materials. Typical lubricants include calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oils, zinc stearate, and combinations comprising at least one of the foregoing lubricants. The flow agent includes, for example, silica.

[0157] Certain dosage forms described herein contain fillers, such as water insoluble fillers, water soluble fillers, and combinations comprising any of the foregoing. The filler can be a water insoluble filler such as silica, titanium dioxide, talc, alumina, starch, kaolin, polacrilin potassium, cellulose powder, microcrystalline cellulose, and combinations comprising any of the foregoing fillers. Typical water-soluble fillers include water-soluble sugars and sugar alcohols, specifically lactose, glucose, fructose, sucrose, mannose, dextrose, galactose, the corresponding sugar alcohols and other sugar alcohols, such as mannitol, sorbitol, xylitol, and combinations comprising any of the foregoing fillers.

[0158] Such dosage forms may be prepared by a variety of conventional mixing, milling and preparation techniques apparent to those skilled in the art of pharmaceutical formulation. Such techniques include, for example, direct compression using suitable punches and dies which fit on a suitable rotary tablet press; injection or compression molding using a suitable mold fitted in a compression unit, followed by granulation and compression; extruding into a mould in a paste form, or extruding and forming into an extrudate to be cut into a certain length,

[0159] the oral dosage form may include an effective amount of a melt-extruded multiparticulate form subunit disposed within a capsule. For example, a plurality of melt-extruded multiparticulates in an amount sufficient to provide an effective release dose upon swallowing and contact with gastric fluid are placed into a gelatin capsule.

[0160] The subunits, i.e., multiparticulate form, can be compressed into oral tablets by conventional tableting equipment using standard techniques. Techniques and compositions for producing tablets (compression and molding), capsules (hard and soft gelatin) can also be found in Remington's pharmaceutical sciences (Aurther Osol. editors), 1553-1593 (1980).

[0161] The composition may be in the form of a microtablet enclosed within a capsule, i.e. a gelatin capsule. For this form, gelatin capsules used in the pharmaceutical formulation art, such as the hard gelatin capsule known as CAPSUGEL from Pfizer, may be used.

[0162] Certain of the dosage forms described herein may be coated dosage forms. The coating may be, for example, a functional or non-functional coating, or a multifunctional and/or non-functional coating. A "functional coating" is intended to include coatings that modify the release characteristics of the overall formulation, such as a sustained release coating. A "non-functional coating" is a coating intended to include non-functional coatings, such as decorative coatings. While non-functional coatings may have some effect on the active agent due to the processes of initial dissolution, hydration, perforation, etc. of the coating, it is not believed that there is a significant difference from non-coated compositions.

[0163] Certain dosage forms described herein may be coated with a functional or nonfunctional coating. The coating may comprise from about 0 to about 40 wt% of the composition. The coating material can comprise a polymer, specifically including film-forming polymers such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxymethylcellulose, cellulose triacetate, cellulose sulfate sodium salt, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), polyethylene, low density polyethylene, high density polyethylene, polypropylene, polyethylene glycol, Polyethylene oxide, poly (ethylene terephthalate), polyvinyl alcohol, polyvinyl isobutyl ether, poly (vinyl acetate), polyvinyl chloride, polyvinyl pyrrolidone, and combinations comprising any of the foregoing.

[0164] To provide a taste masking effect, the polymer may be a water insoluble polymer. The water insoluble polymer includes ethylcellulose or ethylcellulose dispersions, acrylate polymers and/or methacrylate polymers, cellulose acetate, cellulose butyrate or cellulose propionate having a low quaternary amine content, or copolymers of acrylate or methacrylate, and the like, as well as combinations comprising any of the foregoing polymers.

[0165] The inclusion of an effective amount of plasticizer in the coating composition improves the physical properties of the film. For example, ethyl cellulose has a high glass transition temperature and does not form an elastic film under normal coating conditions, so that good results are obtained by adding a plasticizer to ethyl cellulose before it is used as a coating material. Generally, the amount of plasticizer added to the coating solution is based on the polymer concentration, e.g., most often about 1 to 50 weight percent of the polymer. However, the concentration of plasticizer can be determined by routine experimentation.

[0166] Plasticizers for ethylcellulose and other celluloses include, for example, dibutyl sebacate, diethyl titanate, triethyl citrate, tributyl citrate, glycerol triacetate, and combinations comprising at least one of the foregoing plasticizers, however, the use of other water-insoluble plasticizers (such as acetyl monoglycerides, phthalate esters, castor oil, and the like) is also possible.

[0167] Plasticizers for the acrylic polymer include, for example, citric acid esters such as triethyl citrate NF, tributyl citrate, dibutyl titanate, 1, 2-propylene glycol, polyethylene glycol, propylene glycol, diethyl titanate, castor oil, triacetin, and combinations comprising at least one of the foregoing plasticizers, however, it is also possible to use other plasticizers such as acetyl monoglycerides, phthalate esters, castor oil, and the like.

[0168] The functional coating, for example, comprises a coating agent comprising a poorly water permeable component (a) such as an alkyl cellulose, e.g., ethyl cellulose, e.g., AQUACOAT (30% dispersion produced by philadelphia FMC corporation) or surerelease (25% dispersion, Colorcon corporation, West Point, PA) and a water soluble component (b) such as a substance capable of forming a channel through the poorly water permeable component after hydration or dissolution thereof. Specifically, the water soluble component is a low molecular weight polymeric material such as hydroxyalkyl cellulose, hydroxyalkyl (alkylcellulose), and carboxymethyl cellulose or salts thereof. Specific water-soluble polymeric materials include, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and combinations comprising at least one of the foregoing. The water soluble component may comprise hydroxypropyl methylcellulose, such as methocel (dow). The water soluble component has a relatively low molecular weight, specifically a molecular weight of less than or equal to about 25,000, or less than or equal to about 21,000.

[0169] In the functional coating, the weight ratio of the total water-soluble fraction (b) to the poorly water-permeable fraction (a) (b) to (a) is about 1: 4 to 2: 1, specifically about 1: 2 to 1: 1, and more specifically about 2: 3. While the ratios disclosed herein are ideal for achieving the release rate goals of dosage forms currently on the market, other ratios may be used to vary the rate at which the coating allows release of the active agent. The functional coating may comprise about 1-40 wt%, specifically about 3-30 wt%, more specifically about 5-25 wt%, and still more specifically about 6-15 wt% of the total formulation.

[0170] The coating may be applied to the dosage form using any suitable method. Examples of methods which can be used are the single-or double-agglomeration method, the interfacial polymerization method, the liquid drying method, the temperature and ionic gelation method, the spray drying method, the spray cooling method, the fluidized bed coating method, the plate coating method, the electrostatic deposition method.

[0171] The coating can be any thickness, specifically, about 0.005 μm to 25mm thick, more specifically, about 0.05 μm to 5mm thick.

[0172] Herein, the pharmacokinetic profile of a typical dosage form (e.g., containing extended release quinine particles) is characterized by rapid onset, peak to trough levels. The dosage form can be formulated to have a dissolution profile that is substantially independent of pH or dependent on pH (e.g., an enterically coated dosage form).

[0173] In one embodiment, the dosage form exhibits a dissolution profile such as: the dosage form is mixed with 900ml of purified water at 37 ℃. + -. 0.5 ℃ at 75rpm pulp speed, at 60 minutes, according to USP28<711> test method 2 (pulp), the quinine release amounting to about 20-40% by weight of the total quinine content, and after 10 hours, the quinine release amounting to about 80% or more than 80% of the total quinine content.

[0174] In another embodiment, the dosage form exhibits a dissolution profile such as: the dosage form is mixed with 900ml of purified water at 37 ℃. + -. 0.5 ℃ at 75rpm pulp speed, according to USP28<711> test method 2 (pulp), at 60 minutes the quinine release amounts to about 10-30% by weight of the total quinine content, and after 10 hours the quinine release amounts to about 70% or more than 70% of the total quinine content.

[0175] In yet another embodiment, the dosage form exhibits a dissolution profile such as: the dosage form is mixed with a 0.1N hydrochloric acid medium at 37 ℃. + -. 0.5 ℃ according to USP28<711> test method 1 or 2, and after 2 hours the amount of quinine released is about 0-10% by weight of the total amount of quinine, the medium is exchanged for a buffer phase or water at pH4.5, 6.8, 7.0, and after 2 hours the amount of quinine released is about 0-100% by weight of the total amount of quinine.

[0176] In another embodiment, the dosage form exhibits a dissolution profile such as: the dosage form is mixed with a 0.1N hydrochloric acid medium at 37 ℃. + -. 0.5 ℃ according to USP28<711> test method 1 or 2, and after 2 hours the quinine release amounts to about 0-50 wt% of the total quinine content, and the medium is exchanged for a buffer phase or water at pH4.5, 6.8, 7.0, and after 2 hours the quinine release amounts to about 0-100 wt% of the total quinine content.

[0177]In another embodiment, the sustained release quinine formulation is capable of achieving T at about 1.5-8 hours_maxSpecifically about 3 to 7 hours, more specifically about 5 to 6 hours. After administration of a sustained-release quinine preparation containing about 300-600mg quinine, C_maxAbout 200-5000 ng/mL, specifically about 500-3000 ng/mL; and, at steady state, C at 12-24 hours_minAbout 100 ng/ml and 3500 ng/ml.

[0178]In another embodiment, the sustained release quinine formulation has pharmacokinetic characteristics of: c_maxOf about 50% or more than 50% for a period of about 10-20 hours. In addition, the pharmacokinetic profile of the sustained release quinine formulation is: c_maxOf about 80% or more than 80% for a duration of about 2-12 hours.

[0179] The formulation is administered 1 time per day to release a therapeutically effective amount of quinine in a patient within 16 hours, specifically 18 hours, more specifically 24 hours.

[0180] In one embodiment, the sustained release formulation has a higher bioavailability than a corresponding immediate release formulation. Thus, lower doses of active agent can be used in sustained release formulations, while higher doses of active agent in immediate release formulations achieve the same bioequivalence.

[0181] In one embodiment, the sustained release quinine solid oral dosage form may contain from about 50 to about 1000mg quinine per dosage unit, more specifically, about 100 to about 750mg quinine, and even more specifically, about 250 to about 500mg quinine per dosage unit.

[0182] In one embodiment, the sustained release solid oral dosage form of quinine may contain about 350-: 3 times daily, 2 units each time, or 2 times daily, 2 or 3 units each time, or 1 time daily, 3 or 4 units each time.

[0183] In another embodiment, the sustained release solid oral dosage form of quinine may contain about 100-400mg quinine per dosage unit, more specifically about 150-350mg quinine, still more specifically about 200-300mg quinine, used in amounts of: 1, 2 or 3 times daily, 1, 2, 3 or 4 units per dose.

[0184] In another embodiment, the sustained release solid oral dosage form of quinine may contain about 200-600mg quinine sulfate, more specifically about 260-520mg quinine, still more specifically about 300-450mg quinine,

[0185] also included herein are pharmaceutical kits, for example, for treating parasitic diseases (e.g., simple malarial falciparum malaria, severe or complex malarial falciparum malaria), treating and preventing leg cramps, or treating babesiosis caused by babesia microti, comprising one or more containers containing a sustained release dosage form of quinine or a salt thereof. The kit may further comprise one or more conventional pharmaceutical kit components, such as one or more containers that help facilitate compliance with a particular dosage regimen; one or more carriers; printed instructions, either as inserts or as labels, indicate the amount of component to be administered and/or the administration regimen. A typical kit may be in the form of a blister pack which may be arranged in the desired order for a particular dosage regimen. Suitable blister pack packaging arranged in a variety of configurations to accommodate a particular dosage regimen are well known in the art or readily apparent to those of ordinary skill in the art.

[0186] In one embodiment, the quinine controlled release formulation package is printed with information warning that quinine may cause QT/QTc prolongation of adverse reactions in certain patients.

[0187] Those liquids, solutions, emulsions or suspensions may be packaged in a manner that is easy for children or elderly patients to administer. For example, prefilled drops (e.g., eye drops, etc.), prefilled injections, and similar containers filled with the sustained release quinine formulation liquids, solutions, emulsions, or suspensions are also contemplated herein.

[0188] In one embodiment, where the carboxyvinyl polymer is included in the controlled-release quinine formulation, the formulation is free of polyethylene glycol, and in particular, free of polyethylene glycol having a molecular weight of about 900-. In another embodiment, the controlled-release quinine formulation does not contain polymers or cross-linkers for thiol groups. In another embodiment, the controlled-release quinine formulation does not contain a combination of low molecular weight polyethylene glycol (molecular weight of about 100,000-900,000), high molecular weight polyethylene glycol (e.g., molecular weight of about 1,000,000-9,000,000) and starch or starch derivatives. In another embodiment, the controlled-release quinine formulation does not contain a chemotherapeutic agent when the biodegradable polymer is present in the formulation. In another embodiment, the quinine controlled-release formulation lacks Eudragit RS, an acrylic and methacrylic ester copolymer having about 4-7% amine groups.

[0189] In another embodiment, the controlled-release quinine formulation is free of microcapsules encapsulated, coated or surrounded by anionic or cationic polymers. In one embodiment, the controlled release quinine formulation contains only the controlled release portion and no immediate release portion. In one embodiment, the controlled-release quinine formulation comprises a methacrylic acid and methacrylate copolymer and a polymer that does not contain quaternary ammonium groups. In one embodiment, the controlled-release quinine formulation is pectin-free. In another embodiment, the controlled-release quinine formulation is free of polyvinyl alcohol and methacrylic acid copolymers.

[0190] In another embodiment, the controlled-release quinine formulation does not contain a hydroxypropyl methylcellulose matrix or a matrix comprising a 1: 1 combination of hydroxypropyl methylcellulose and carboxymethyl cellulose matrices. In one embodiment, the controlled-release quinine formulation contains only quinine active agents. In one embodiment, the controlled release quinine formulation is in a non-liposomal form. In another embodiment, the controlled-release quinine formulation does not contain lipid encapsulated particles. In another embodiment, the controlled release quinine formulation is not a coated tablet prepared from an aqueous dispersion of an acrylic polymer emulsion, such as Eudragit L100-55, Eudragit L100, or Eudragit S100; or emulsion polymer Eudragit L30D or Eudragit E30D

[0191] In one embodiment, administration of the controlled-release quinine formulation to a patient results in a baseline prolongation of the patient's average QT/QTc interval from less than about 20ms, specifically less than about 10ms, more specifically less than about 5 ms.

[0192] In one embodiment, a therapeutically effective amount of quinine in a controlled release formulation is an amount sufficient to significantly reduce the risk of prolonged cardiac QT intervals or other undesirable side effects as described above in the subject being treated, while achieving the desired therapeutic effect. A significant decrease refers to any detectable negative change that is statistically significant in the standard parameter test of statistical significance-the student T test (p < 0.05).

[0193] The following examples further illustrate the invention and, of course, should not be construed as in any way limiting its scope.

Examples

Example 1 quinine sulfate sustained Release formulation, dihydrate (cinchonin-9-ol, 6' -methoxy-, (8 α, 9R) -, sulfate (2: 1), dihydrate)

Example 1:

composition (I)	Weight (mg)	Weight (mg)
			Quinine sulfate dihydrate	490	650
Carbopol 971P NF Polymer	460	500
			Lactose monohydrate	40	40
Talc	5	5
Lubricant agent
			Magnesium stearate	5	5
			Total amount of	1000	1200

[0194] The ingredients other than the lubricant were mixed in a high shear granulator. Water is added, the wet mixture is granulated, the granules are sieved, dried and ground. And adding the particles into a low-shear stirrer, adding a lubricant, and stirring. The final blend is compressed in a tablet press to form a quinine sustained release dosage form.

Example 2:

composition (I)	Weight (mg)	Weight (mg)
			Quinine sulfate dihydrate	490	650
Hydroxypropyl methylcellulose	460	500
			Lactose monohydrate	40	40
			Flow agent
Silica colloids	5	5
Lubricant agent
			Magnesium stearate	5	5
			Total amount of	1000	1200

[0195] The components other than the lubricant and the flow agent were mixed in a low shear mixer for 20 minutes. Adding lubricant and flow agent, and stirring for 5 min. Direct compression in a tablet press.

Example 3:

composition (I)	Weight (mg)	Weight (mg)
			Quinine sulfate dihydrate	490	650
Hydroxypropyl methylcellulose	200	250
			Hydroxyethyl cellulose	260	290
Lactose monohydrate	40	0

			Flow agent
Silica colloids	5	5
Lubricant agent
			Magnesium stearate	5	5
			Total amount of	1000	1200

[0196] The ingredients other than the lubricant were mixed in a high shear granulator. Water and ethanol were added as granulating solutions, the wetted mixture was granulated, and then the granules were sieved, dried and ground. Then adding the granules into a low-shear mixer, adding a flow agent and a lubricant, and stirring. The final blend is compressed in a tablet press.

Example 4: controlled release coated pellets or beads

Composition (I)	Weight (g)
		Quinine sulfate dihydrate	9000
Microcrystalline cellulose	800
Lubricant agent
		Magnesium stearate	200
		Total amount of	10,000

[0197] The components other than the lubricant were mixed in the high shear mixer for 10 minutes. Add lubricant and stir for 3 minutes. Directly compressed into tablets or pellets or beads. Pellets or beads can also be prepared by extrusion spheronization, wherein the wetted composition can be extruded alone or with the aid of fillers, flow agents or lubricants.

Controlled release coating

Composition (I)	％
		Methacrylic acid copolymer	15
Polyethylene glycol 600	1
		Talc	4
Water/ethanol	80 process of removing

[0198] Polyethylene glycol was added to the water/ethanol dispersion of methacrylic acid copolymer. Talc was added while stirring with a propeller mixer.

[0199] The pellets or beads are added to a porous coating plate or fluidized bed with a Wurster insert unit. The coating is sprayed onto the pellets or beads. Coating levels of about 5-20% coating weight are applied.

[0200] The coated pellets or beads are loaded into a capsule shell.

Example 5: sustained release wax formulations

Composition (I)	Weight (mg)	Weight (mg)
			Quinine sulfateDihydrate of a mineral acid	490	650
Carnauba wax	460	500
			Microcrystalline cellulose	40	40

Flow agent
			Silica colloids	5	5
			Lubricant agent
Magnesium stearate	5	5
Total amount of	1000	1200

[0201] The ingredients other than the lubricant and flow agent are mixed in a high shear granulator. Water and ethanol were added, the wetted mixture was granulated, and the granules were sieved, dried and ground. Then adding the granules into a low-shear mixer, adding a flow agent and a lubricant, and stirring. The final blend is compressed in a tablet press.

Example 6 QTc interval measurement of a single dose of quinine sulfate

[0202] A study was conducted on healthy volunteers to measure QTc interval for a single dose of quinine sulfate. One study was to ascertain the effect of food on an oral single dose of 324mg oral capsules (324mg quinine sulfate, 82mg corn starch, 40mg talc, 4mg magnesium stearate). The second study was to compare two dose levels, a single oral dose of 324mg quinine sulfate with a single oral dose of 648mg quinine sulfate (two capsules), both cases being performed under fasting conditions. Electrocardiographic intervals were repeatedly measured on 50 subjects aged 18-47 years, 24 men and 26 women. The results are shown in Table 1 below and FIGS. 1-4, which show the correlation of the mean maximum QTc interval prolongation results with the mean peak plasma quinine concentration.

TABLE 1

Time (hours)

Study 1A: 324mg of sulfuric acid

Study 1B: 324mg quinic sulfate

Study 2C: 324mg of sulfuric acid

Study 2D: 648mg of sulfuric acid

	Quinine capsule, fasting		Ning capsule, food intake		Quinine capsule, fasting		Quinine capsule, fasting
										Mean plasma concentration (ng/ml); QTc (msec)
	(ng/ml)	(msec)	(ng/ml)	(msec)	(ng/ml)	(msec)	(ng/ml)	(msec)
									0	0	399	0	397	0；	404	0	410
2	2040	402	835	397	1860	415	2808	422
									4	1971	399	2265	396	1877	414	2946	422
6	1718	400	2013	402	1707	411	2721	419
									12	990	398	1216	400	994	411	1705	417
24	473	399	543	400	475	409	912	412

[0203] The data shown in columns a and B of table 1 are mean plasma measured concentrations and QTc measurements 24 hours after administration of a single oral dose of 324mg quinine sulfate capsules under fasting (a) and fed (B) conditions. The data shown in column C of table 1 are mean plasma measured concentrations and QTc measurements 24 hours after oral administration of a single dose of 324mg quinine sulfate capsules under fasting conditions. The data shown in column D of table 1 are mean plasma measured concentrations and QTc measurements 24 hours after oral administration of a single dose of 324mg quinine sulfate capsules under fasting conditions.

[0204] As shown by the data in the table, the QTc mean increases, corresponding to the peak quinine plasma concentration, which peaks at an average of 2.4-4.4 hours after oral administration in the fasted state and 4-6 hours when taken with food. The mean QTc value increased more when a single dose of 648mg was administered and the same dose (higher peak concentration) was administered with food than the 324mg dose. In this study, the QTc interval was significantly extended (> 450msec) for 7 subjects. It can be observed from the figure that the higher the blood quinine level, the greater the chance of prolongation of the QTc interval. While not wishing to be bound by theory, it is believed that controlling blood quinine levels such that the peak in plasma quinine concentration is reduced or eliminated may reduce or eliminate the chance of QTc prolongation.

Example 7 non-Linear dose-Effect relationship for Single dose administration of quinine sulfate

[0205]A study was conducted on healthy volunteers, i.e., 1 and 2 capsules containing 324mg of quinine sulfate (324mg quinine sulfate, 82mg corn starch, 40mg talc, 4mg magnesium stearate per capsule) were orally administered in a single dose in the fasted state, and then AUC (0-24 hours and 0-INF) and C were measured_maxThe study subjects were 24 persons. After the above dose was taken, blood samples were taken every half hour for the first 4 hours and then every hour until 48 hours. Ln-transformed data, geometric mean, and least squares means, untransformed data of the results were calculated. The geometric mean is calculated on the basis of the least-squares mean of the ln-transformed values. The results in Table 2a below show the C produced after doubling the dose under fasting conditions_maxLower than expected from a linear dose-effect relationship indicates a non-linear dose-effect relationship with dose. C obtained by multiplying plasma concentration in 1 capsule treatment by 2_maxSummarized in Table 2a, which is C obtained in 2-pellet capsule therapy_max129% of the data, take the 90% confidence interval in 122-138%. AUC_tAnd AUC_infShowing a proportional increase after taking two capsules.

TABLE 2a

PK variable	324mg quinine sulfate, 1 capsule*(dose adjustment 2X324mg)	648mg quinine sulfuric acid, 2 capsules*	% ratio	90% confidence interval (lower, upper limit)	Product effect P-value
						Ln-transformed data, geometric mean
Cmax(ng/ml)	4126.31	3174.89	129.97	(122.15，138.29)	＜0.0001
						AUC0-t(ng-hr/ml)	61186.53	54440.26	112.39	(106.56，118.54)	0.0011
AUC0-INF(ng-hr/ml)	66715.41	59166.93	112.76	(105.69，120.3)	0.0044
						Untransformed data, least squares means
Cmax(ng/ml)	4247.02	3243.11	130.96	(123.28，138.63)	＜0.0001
						AUC0-t	64277.02	56394.65	113.98	(108.03，119.93)	0.0006

(ng-hr/ml)
						AUC0-INF(ng-hr/ml)	70886.14	61817.27	114.67	(107.37，121.97)	0.0023
Tmax	2.78	2.80	99.25	(84.8，113.7)	0.9298
						kelim	0.0592	0.0572	103.48	(94.67，112.28)	0.5045
t1/2	12.76	12.80	99.67	(85.69，113.66)	0.9683

^*The capsules contain quinine sulfate USP, corn starch, magnesium stearate and talc.

Example 8 dose-response relationship between Single and Low doses of quinine sulfate

[0206]A pediatric study was conducted on healthy volunteers, i.e., AUC (0-24 hours and 0-INF) and C were measured in the fasted state for oral single doses of 260mg quinine sulfate and 324mg quinine sulfate (1.25-fold lower dose of 260 mg) and C_maxThe study subjects were 24 persons. After the administration of the above dosage, the composition is,blood samples were taken every half hour for the first 4 hours, then every hour, and again every hour for up to 8 hours, then 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, and 46 hours each. The Ln-transformed data, geometric mean, and least squares means, untransformed data of the results are calculated. The geometric mean is calculated on the basis of the least-squares mean of the ln-transformed values. The results in Table 2a below show a linear dose-response relationship when quinine sulfate is administered at low doses of 360mg and 324 mg.

Table 2b.

PK variable	260mg quinine sulfate, 1 capsule*(dose adjustment 1.25X 324mg)	324mg quinine sulfate, 1 capsule*	% ratio	90% confidence interval (lower, upper limit)	Product effect P-value
						Ln-transformed data, geometric mean
Cmax(ng/ml)	2251.55	2242.70	100.39	(95.8，105.21)	0.8861
						AUC0-t(ng-hr/ml)	30019.28	30318.55	99.01	(93.83，104.48)	0.7535

AUC0-INF(ng-hr/ml)	32072.92	32111.76	99.88	(94.4，105.67)	0.9708
						Untransformed data, least squares means
Cmax(ng/ml)	2310.90	2275.46	101.56	(95.93，107.19)	0.6384
						AUC0-t(ng-hr/ml)	31285.26	31298.12	99.96	(94.63，105.28)	0.9895
AUC0-INF(ng-hr/ml)	33582.46	33280.89	100.91	(95.36，106.46)	0.7811
						Tmax	2.61	2.75	95.04	(84.53，105.55)	0.4255
kelim	0.0615	0.0668	92.05	(85，99.04)	0.0641
						t1/2	11.94	11.13	107.27	(100.34，114.2)	0.0856

^*The capsules contain quinine sulfate USP, corn starch, magnesium stearate and talc.

[0207] Examples 7-8 demonstrate that high doses of quinine do not show a dose-effect relationship, while low doses show a dose-effect relationship, which indicates that controlled release formulations need to be used to achieve lower, more sustained plasma levels. By controlling the quinine release, sharp plasma peaks and valleys can be avoided, thereby ensuring the safety of quinine administration.

[0208] The terms "a" and "an" herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"). All ranges directed to the same component or property are inclusive and independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention, the terms wt%, etc. are equivalent and interchangeable.

[0209] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (40)

1. A controlled release formulation comprising:

a therapeutically effective amount of quinine and a release retarding material;

wherein the release retarding material is a release retarding matrix, a release retarding coating, or a combination comprising at least one of the foregoing; and is

Wherein the controlled release formulation maintains a therapeutically effective steady state plasma level for greater than about 12 hours after administration.

2. A controlled release formulation comprising:

a therapeutically effective amount of quinine and a release retarding material;

wherein the release retarding material is a release retarding matrix, a release retarding coating, or a combination comprising at least one of the foregoing; and is

Wherein the controlled release formulation is administered such that the severity of or the elimination of adverse side effects caused by administration of the immediate release quinine formulation is reduced.

3. The formulation of claim 2, wherein the adverse side effect is cinchona poisoning, tinnitus, blurred vision, thrombocytopenia, granulomatous hepatitis, skin rash, acute interstitial nephritis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, QT interval prolongation, QTc interval prolongation, agranulocytosis, hypoprothrombinemia, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, headache, review, thought disorder, mental state changes, seizures, coma, pruritus, skin flushing, sweating, episodic facial edema, rash, urticaria, erythema multiforme, purpura, light sensitivity, contact dermatitis, acromelic gangrene, cutaneous vasculitis, asthma, tachycardia, arrhythmia, ventricular premature beat, premature beat complicated by ventricular premature beat, PR normal, PR, interstitial syndrome, and so forth, U-wave of QRS and QT interval, ventricular fibrillation, arrhythmia, nausea and vomiting, abdominal pain, diarrhea, visual disorders including sudden visual loss, blindness, decreased visual field, fixed nipple expansion, color vision disorders, hearing loss, deafness, or a combination comprising at least one of the foregoing adverse side effects.

4. The formulation of claim 2, wherein the adverse side effect is QT interval prolongation or QTc interval prolongation.

5. The formulation of claim 2, wherein the controlled release formulation does not cause significant QT prolongation as specified by the standards of the U.S. food and drug administration after administration.

6. The formulation of claim 1, wherein the quinine is quinine sulfate, quinine sulfate dihydrate, quinine hydrochloride, quinine dihydrochloride, or a combination comprising at least one of the foregoing.

7. The formulation of claim 1, comprising a release retarding matrix and a release retarding coating.

8. The formulation of claim 1, wherein the release retarding matrix is an acrylic acid or acrylate polymer, an acrylic acid or acrylate copolymer, an alkyl cellulose, shellac, zein, a hydrogenated vegetable oil, a hydrogenated castor oil, polyvinylpyrrolidone, a crosslinked polyvinylpyrrolidone, a vinyl acetate copolymer, polyethylene oxide, a wax, a digestible long chain substituted or unsubstituted hydrocarbon, a fatty alcohol, fatty acids, fatty acid esters, hydrogenated fats and oils, polymers or copolymers of lactic acid or glycolic acid, polyalkylene glycols, hydroxyalkyl cellulose, crosslinked hydroxyalkyl cellulose, carboxyalkyl cellulose, crosslinked carboxyalkyl cellulose, hydroxyalkyl alkyl cellulose, carboxyalkyl starch, polyvinyl alcohol, potassium methacrylate/divinylbenzene copolymer, or a combination comprising at least one of the foregoing release retarding materials.

9. The formulation of claim 8, wherein the acrylic polymer is an acrylic acid and methacrylic acid copolymer, a methyl methacrylate copolymer, an ethoxyethyl methacrylate, a cyanoethyl methacrylate, an aminoalkyl methacrylate copolymer, a poly (acrylic acid), a poly (methacrylic acid), a methacrylic acid-alkylamide copolymer, a poly (acrylate), a polymethyl methacrylate, a poly (methyl methacrylate), a poly (methacrylic anhydride), a polyacrylamide, a glycidyl methacrylate copolymer, or a combination comprising at least one of the foregoing polymers;

wherein the alkyl cellulose is methyl cellulose, ethyl cellulose, or a combination comprising at least one of the foregoing alkyl celluloses;

wherein the carboxyalkyl cellulose or croscarmellose is croscarmellose sodium, carboxymethyl cellulose, or a combination comprising at least one of the foregoing;

wherein the carboxyalkyl cellulose, cross-linked carboxyalkyl cellulose, or hydroxyalkylalkyl cellulose is hydroxypropyl cellulose, cross-linked hydroxypropyl cellulose, high molecular weight hydroxypropyl methylcellulose, low molecular weight hydroxypropyl methylcellulose, medium viscosity hydroxypropyl methylcellulose, or a combination comprising at least one of the foregoing;

wherein the polyvinyl alcohol is a high molecular weight polyvinyl alcohol, a low molecular weight polyvinyl alcohol, a medium viscosity polyvinyl alcohol, or a combination comprising at least one of the foregoing;

wherein the wax is beeswax, sugar wax, castor wax, carnauba wax, or a combination comprising at least one of the foregoing waxes; and

wherein the carboxyalkyl starch is carboxymethyl starch.

10. The formulation of claim 1, wherein the release-retarding coating is an alkyl cellulose, a hydroxyalkyl alkyl cellulose, a carboxyalkyl alkyl cellulose, a carboxyalkyl cellulose ester, a starch, a polysaccharide, a carrageenan, a galactomannan, traganth, agar, gum arabic, guar gum, xanthan gum, an acrylic or acrylate polymer, polyvinyl alcohol, polyvinyl pyrrolidone, a copolymer of polyvinyl pyrrolidone and vinyl acetate, a polyalkylene oxide, or a combination comprising at least one of the foregoing release-retarding coatings; the coating optionally further comprises a plasticizer.

11. The formulation of claim 10, wherein the release-retarding coating is methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, carboxymethylethylcellulose, alginic acid alkali metal salts, alginates salts, polyethylene oxide, polypropylene oxide, ethylene oxide-propylene oxide copolymers, polyacrylic acid, polymethacrylic acid, methacrylate copolymers, or a combination comprising at least one of the foregoing release-retarding coatings.

12. The formulation of claim 1, wherein the controlled release coating is coated on a granule, particle, tablet, bead, or a combination comprising at least one of the foregoing.

13. The formulation of claim 1, wherein the controlled release formulation further comprises an enteric coating, a non-functional coating, or a combination comprising at least one of the foregoing coatings.

14. The formulation of claim 1, wherein the controlled release formulation is an oral-based formulation that is a tablet, a capsule, a liquid, a suspension, an emulsion, an orally disintegrating tablet, a chewable tablet, an enteric capsule, an osmotic pump, or a combination comprising at least one of the foregoing.

15. The formulation of claim 1, wherein the controlled release formulation comprises quinine granules, quinine particles or quinine beads dispersed in a release-retarding matrix; the beads optionally comprise an inert matrix coated with quinine.

16. The formulation of claim 15, wherein the granules, particles or beads are coated with a release retarding coating.

17. The formulation of claim 16, wherein the controlled release formulation comprises a portion of immediate release quinine.

18. The formulation of claim 17, wherein the immediate release quinine moiety is in the form of a coating, granule, particle, or bead, or a combination comprising at least one of the foregoing.

19. The formulation of claim 1, wherein the controlled release formulation is a parenteral dosage form or a long-acting dosage form.

20. The formulation of claim 1, wherein the controlled release formulation is a taste masked dosage form.

21. The formulation of claim 1, further comprising tetracycline, doxycycline, clindamycin, sulfadoxine/pyrimethamine, or a combination comprising at least one of the foregoing active agents.

22. The formulation of claim 1, wherein quinine is the only active agent in the formulation.

23. The formulation of claim 1, wherein the controlled release formulation maintains therapeutically effective steady state plasma levels for greater than about 16 hours after administration.

24. The formulation of claim 1, wherein the controlled release formulation maintains therapeutically effective steady state plasma levels for greater than about 18 hours after administration.

25. The formulation of claim 1, wherein the quinine controlled release formulation has a T_maxAbout 1.5 to about 8 hours.

26. The formulation of claim 1, wherein, at steady state, C is 12-24 hours_maxAbout 200 ng/ml, C_minAbout 100 ng/ml and 3500 ng/ml.

27. The formulation of claim 1, wherein C_maxOf about 50% or more than 50% for a period of about 10-20 hours.

28. The formulation of claim 1, wherein C_maxOf about 80% or more than 80% for a duration of about 2-12 hours.

29. The formulation of claim 1, wherein the formulation is formulated in a unit dosage form exhibiting a dissolution profile that is: mixing the dosage form with 900ml dissolution medium at 37 ℃ + -0.5 ℃ according to USP28<711> test method 2 (syrup), at a syrup speed of 75rpm, at 60 minutes, the amount of quinine released is about 20-40% by weight of the total quinine; after 10 hours, the quinine release amount is about 80% or more than 80% of the total quinine amount.

30. The formulation of claim 1, wherein the formulation is formulated in a unit dosage form exhibiting a dissolution profile that is: mixing the dosage form with 900ml dissolution medium at 37 ℃ + -0.5 ℃ according to USP28<711> test method 2 (syrup), at a syrup speed of 75rpm, at 60 minutes, the amount of quinine released is about 10-30 wt% of the total quinine; after 10 hours, the quinine release amount is about 70% or more than 70% of the total quinine amount.

31. The formulation of claim 1, wherein the formulation is formulated in a unit dosage form exhibiting a dissolution profile that is: mixing the dosage form with 900ml of purified water at 37 ℃ + -0.5 ℃ according to USP28<711> test method 2 (slurry), at 75rpm slurry speed, at 60 minutes, the amount of quinine released is about 20-40 wt% of the total quinine; after 10 hours, the quinine release amount is about 80% or more than 80% of the total quinine amount.

32. The formulation of claim 1, wherein the formulation is formulated in a unit dosage form exhibiting a dissolution profile that is: mixing the dosage form with 900ml of purified water at 37 ℃ + -0.5 ℃ according to USP28<711> test method 2 (slurry), at 75rpm slurry speed, at 60 minutes, the amount of quinine released is about 10-30 wt% of the total quinine; after 10 hours, the quinine release amount is about 70% or more than 70% of the total quinine amount.

33. The formulation of claim 1, wherein the formulation is formulated in a unit dosage form exhibiting dissolution characteristics such as: (ii) the dosage form, when mixed with 900ml of 0.1N hydrochloric acid medium at 37 ℃ ± 0.5 ℃ for 2 hours according to USP28<711> test method 1 or 2, releases about 0-10 wt% of total quinine; after changing the medium to a buffer phase of pH4.5, 6.8, 7.0 or water for 2 hours, the amount of quinine released is about 0-100% by weight of the total quinine.

34. The formulation of claim 1, wherein the formulation is formulated in a unit dosage form exhibiting dissolution characteristics such as: according to USP28<711> test method 1 or 2, the dosage form releases about 0-50 wt% of total quinine 2 hours after mixing with 900ml of 0.1N hydrochloric acid medium at 37 ℃. + -. 0.5 ℃, and about 0-100 wt% of total quinine 2 hours after changing the medium to a buffer phase of pH4.5, 6.8, 7.0 or water.

35. A kit comprising a plurality of pharmaceutical products comprising the controlled release formulation of claim 1.

36. A method of treating a patient comprising:

administering to a patient the controlled release formulation of claim 1.

37. The method of claim 36, wherein the step of administering is for the purpose of treating or preventing malaria, leg cramps, or babesiosis caused by babesia microti.

38. A controlled release formulation comprising:

a therapeutically effective amount of quinine and a release retarding material;

wherein the release retarding material is a release retarding matrix, a release retarding coating, or a combination comprising at least one of the foregoing;

wherein the release-retarding matrix is an alkyl cellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, vinyl acetate copolymer, wax, digestible long-chain substituted or unsubstituted hydrocarbon, fatty alcohol, fatty acid ester, hydrogenated oil, crosslinked hydroxyalkyl cellulose, polyvinyl alcohol, or a combination comprising at least one of the foregoing release-retarding materials; and is

Wherein the release-retarding coating is an alkyl cellulose, a hydroxyalkyl alkylcellulose, a starch, a polysaccharide, agar, gum arabic, guar gum, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone and vinyl acetate, a polyalkylene oxide, or a combination comprising at least one of the foregoing release-retarding coatings; wherein the coating optionally further comprises a plasticizer.

39. The formulation of claim 36, wherein the matrix further comprises polyethylene oxide, polyalkylene glycol, an acrylic acid or acrylate polymer, an acrylic acid or acrylate copolymer, a polymer or copolymer of lactic acid or glycolic acid, a crosslinked carboxyalkyl cellulose, a carboxyalkyl starch, a potassium methacrylate/divinylbenzene copolymer, a carboxyalkyl cellulose, a hydroxyalkylalkyl cellulose, a hydroxyalkylcellulose, or a combination comprising at least one of the foregoing;

wherein the release-retarding coating further comprises an acrylic acid or acrylate polymer, a carboxyalkyl cellulose, a carboxyalkyl alkyl cellulose, a carboxyalkyl cellulose ester, carrageenan, galactomannan, traganth, or a combination comprising at least one of the foregoing.

40. A fast dissolving tablet formulation comprising quinine.