CA2438641A1 - Stabilized pharmaceutical and thyroid hormone compositions and method of preparation - Google Patents
Stabilized pharmaceutical and thyroid hormone compositions and method of preparation Download PDFInfo
- Publication number
- CA2438641A1 CA2438641A1 CA002438641A CA2438641A CA2438641A1 CA 2438641 A1 CA2438641 A1 CA 2438641A1 CA 002438641 A CA002438641 A CA 002438641A CA 2438641 A CA2438641 A CA 2438641A CA 2438641 A1 CA2438641 A1 CA 2438641A1
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- sodium
- tablet
- microcrystalline cellulose
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/40—Static mixers
- B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
- B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
- B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/40—Static mixers
- B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
- B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
- B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
- B01F25/4334—Mixers with a converging cross-section
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/80—Falling particle mixers, e.g. with repeated agitation along a vertical axis
- B01F25/82—Falling particle mixers, e.g. with repeated agitation along a vertical axis uniting flows of material taken from different parts of a receptacle or from a set of different receptacles
Abstract
A pharmaceutical composition with B-sheet microcrygtalline cellulose with improved potency life and methods of preparation therefor. Improved thyroid hormone pharmaceutical compositions comprising 50 weight % or more of B-sheet microcrystalline cellulose.
Description
SPECIFICATION
Electronic Version 1.2.8 Stylesheet Version 1.0 Stabilized Pharmaceutical and Thyroid Hormone compositions and Method of Preparation Inventors:
G. Andrew Franz, Elaine A, Strauss, Philip A, DiMenna and Rocco L. Lemma Background of Invention:
[0001] The present . invention relates to solid pharmaceutical compositions and the method of preparing the same. More specifically, the present invention relates to the preparation of stabilized pharmaceutical compositions, using pharmaceutically active ingredients such asv levothyroxine sodium and liothyronine sodium (thyroid hormone drugs), in a solid dosage form. Said stabilized thyroid hormone compositions are prepared by blending the active moiety and B-sheet form of microcrystalline cellulose and compressing to the desii:ed solid dosage forms.
Electronic Version 1.2.8 Stylesheet Version 1.0 Stabilized Pharmaceutical and Thyroid Hormone compositions and Method of Preparation Inventors:
G. Andrew Franz, Elaine A, Strauss, Philip A, DiMenna and Rocco L. Lemma Background of Invention:
[0001] The present . invention relates to solid pharmaceutical compositions and the method of preparing the same. More specifically, the present invention relates to the preparation of stabilized pharmaceutical compositions, using pharmaceutically active ingredients such asv levothyroxine sodium and liothyronine sodium (thyroid hormone drugs), in a solid dosage form. Said stabilized thyroid hormone compositions are prepared by blending the active moiety and B-sheet form of microcrystalline cellulose and compressing to the desii:ed solid dosage forms.
[0002] Thyroid hormone preparations of levothyroxine sodium and liothyronine sodium are pharmaceutical preparations useful to the treatment of hypothyroidism and thyroid hormone replacement therapy in mammals, for example, humans and dogs.
[0003] Thyroid hormone preparations are used to treat reduced or absent thyroid function of any etiology, including human or animal ailments such as myxedema, cretinism and obesity.
[0004] Hypothyroidism is a common condition. It has been reported in the United States Federal Register that Hypothyroidism has a prevalence of 0.5 percent to 1.3 percent in adults. In people over 60, the prevalence of primary hypothyroidism increases to 2.7 percent in men and 7.1 percent in women. Because congenital hypothyroidism may result in irreversible mental retardation, which can be avoided with early diagnosis and treatment, newborn screening for this disorder is mandatory in. North America, Europe, and Japan.
[0005] Thyroid hormone replacement therapy can be a chronic, lifetime endeavor. The dosage is established for each patient individually..Generally, the initial dose Is small, The amount is increased gradually until clinical evaluation and laboratory tests indicate that an optimal response has been achieved. The dose required to maintain this response is then continued. The age and general physical condition of the patient and the severity and duration of hypothyroid symptoms determine the initial dosage and the rate at which the dosage may be increased to the eventual maintenance level. it has been reported that the dosage increase should be very gradual in patients with myxedema or cardiovascular disease to prevent precipitation of angina, myocardial infarction, or stroke.
[0006] It is important that thyroid hormone treatment have the correct:
dosage. Both under treatment and over treatment can have deleterious health impacts. In the case of under treatment, a sub-optimal response and hypothyroidism could result. under treatment has also been reported to be a potential factor in decreased cardiac contractility and increased risk of coronary artery disease. Conversely, over treatment may result in toxic manifestations of hyperthyroidism such as cardiac pain, palpitations, or cardiac arrhythmia's. In patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium may be hazardous in a particular.
dosage. Both under treatment and over treatment can have deleterious health impacts. In the case of under treatment, a sub-optimal response and hypothyroidism could result. under treatment has also been reported to be a potential factor in decreased cardiac contractility and increased risk of coronary artery disease. Conversely, over treatment may result in toxic manifestations of hyperthyroidism such as cardiac pain, palpitations, or cardiac arrhythmia's. In patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium may be hazardous in a particular.
(0007] Hyperthyroidism is a known risk factor for osteoporosis. Several studies suggest that subclinical hyperthyroidism in premenopausal women receiving thyroid hormone drugs for replacement or suppressive therapy is associated with bone loss. To minimize the risk of osteoporosis, it is preferable that the dose be kept to the lowest effective dose.
[0008] Because of the risks associated with over treatment or under treatment with levothyroxine sodium, there is a need for thyroid hormone products that are consistent in potency and bioavailability. Such consistency is best accomplished by manufacturing techniques that maintain consistent amounts of the active moiety during tablet manufacture.
[0009] Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, levothyroxine) sodium or triiodothyronine (T3, liothyronine) Sodium or both. T4 and T3 are produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. T4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T3 contains three atoms of iodine and is formed by the coupling of one molecule of DIT with one molecule of monoiodotyrosine (MIT), Both hormones are stored In the thyroid colloid as thyroglobulin. Thyroid hormone preparations belong to two categories: (1) natural hormonal preparations derived from animal thyroid, and (2) synthetic preparations.
Natural preparations include desiccated thyroid and thyroglobulin.
Natural preparations include desiccated thyroid and thyroglobulin.
(0010] Desiccated thyroid is derived from domesticated animals that are used for food by man (either beef or hog thyroid), and thyroglobulin is derived from thyroid glands of the hog.
The United States Pharmacopoeia (USP) has standardized the total iodine content of natural preparations. Thyroid USP contains not less than (NLT) 0.17 percent and not more than (NMT) 0.23 percent iodine, and thyroglobulin contains not less than (NLT) 0.7 percent of organically bound iodine, Iodine content is only an indirect indicator of true hormonal biologic activity.
The United States Pharmacopoeia (USP) has standardized the total iodine content of natural preparations. Thyroid USP contains not less than (NLT) 0.17 percent and not more than (NMT) 0.23 percent iodine, and thyroglobulin contains not less than (NLT) 0.7 percent of organically bound iodine, Iodine content is only an indirect indicator of true hormonal biologic activity.
(0011] Synthetic forms for both T4 and T3 thyroid hormone are available from a number of producers. For example, liothyronine sodium (T3) tablets are available from Jones Phaxma, St Louis, Missouri under the trademark Cytomel (now King Pharmaceuticals, Inc.) Levothyroxine sodium (T4) is available under the tradename Levoxyl from Jones Pharma (now King Pharmaceuticals, Inc.), under the tradename Synthroid from Knoll Pharmaceutical, Mt. olive, New Jersey, and under the tradename Unithroid from Jerome Stevens Pharmaceuticals, Bohemia, New York. In addition a veterinarian preparation of levothyroxine sodium is available under the tradename Soloxine from Jones Pharma, St.
Louis, Missouri.
Louis, Missouri.
[0012] It is well known that the stability of thyroid hormone drugs are quite poor. They are hygroscopic and degrade in the presence of moisture or light, and under conditions of high temperature, The instability is especially notable in the presence of pharmaceutical excipients, such as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes.
[0013] It is desirable, therefore, to prepare a stabilized dosage of levothyroxine and liothyronine, which will have a longer shelf life that can be used in the treatment of human or animal thyroid hormone deficiency. U.S. Patent No. 5,22.5,204 (the '204 patent) is directed to improving the stability of levothyroxine sodium. In one embodiment disclosed by '204, stabilized levothyroxine sodium was prepared in a dry state by mixing levothyroxine sodium with a cellulose tableting agent using geometric dilution and subsequently combining this mixture with the same or a second cellulose tableting agent, such as microcrystalline cellulose. Other tableting aids or excipients can be used in this formulation, This 'Z04 patent is incorporated by reference herein, in its entirety.
[0014] The microcrystalline cellulose disclosed in '204 is AVICEL 101, 102, 103, 105, trademarks of FMC Company of Newark, DE., and Microcrystalline Cellulose NF, or EMCOCEL, a trademark owned by Penwest Pharmaceuticals of Patterson, NY. These microcrystalline cellulose products are prepared by re-slurrying the cellulose and spray-drying the product, This produces an a-helix spherical mierocrystalline cellulose product.
[0015] U. S. Patents 5 ,95 5,105 and 6,05 6,975 (the continuation of '105) disclose a stabilized pharmaceutical preparation of levothyroxine and microcrystalline cellulose, along with other excipients. The microcrystalline cellulose products used by ' 1 OS and '975 were also the a-form Avicel microcrystalline cellulose products. U. S. Patents 5 ,95 5,105 and 6,05 6.975 are incorporated by reference herein, in their entirety.
[0016] The microcrystalline cellulose product of the present invention is prepared by making a wet cake and drying it with a drum dryer, then passing the dried product through a screen or mill for sizing, which produces a a -sheet form microcrystalline cellulose which has a flat needle shape. Such 5 -sheet microcrystalline cellulose is marketed under the trademark CEOLUS KG801 by FMC Company of Newark. Del. Said Ceolus product has different morphology, and therefore different performance characteristics, than those of the Avicel product, and is suitable for preparing the present stabilized pharmaceutical product.
[0017] The B-sheet microcrystailine cellulose of the present invention is disclosed in U.S_ Patent 5,574,150, which is hereby incorporated by reference. Further disclosure relating to B-sheet microcrystalline cellulose is found in International Journal of Pharmaceutics 182 (199) 155 which is hereby incorporated by reference.
[0018] The Ceolus product (B-sheet microcrystalline cellulose) is disclosed by FMC in its product bulletin dated October 1997 as being suitable for "smaller size tablets" and "exceptional drug carrying capacity." Said Ceolus product was to provide superior compressibility and drug loading capacity that still exhibited effective flowability. The examples given in the bulletin are of vitamin C combined with Ceolus microcrystalline cellulose at levels of from 30 to 45 weight % Ceolus product in the form of a tablet, At higher levels of Ceolus product concentration, flow problems were encountered In the process of compressing tablets, and the Ceolus product was deemed unsuitable for compressions at higher concentrations than about 45 weight %.
[0019] None of the references listed above disclose the present invention of a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine, and at least about 50 weight % the B-sheet form of microcrystalline cellulose.
Summary of Invention [0020] The present invention relates to a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine, and the B-sheet form of microcrystalline cellulose, in the form of a solid dosage. More specifically, the present invention relates to a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine sodium and/or liothyronine sodium, at least about 50 weight % of the dosage weight composed of the B-sheet form of microcrystalline cellulose, and, optionally, additional excipients, in a solid dosage form.
Summary of Invention [0020] The present invention relates to a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine, and the B-sheet form of microcrystalline cellulose, in the form of a solid dosage. More specifically, the present invention relates to a stabilized pharmaceutical composition comprising a pharmaceutically active ingredient, such as levothyroxine sodium and/or liothyronine sodium, at least about 50 weight % of the dosage weight composed of the B-sheet form of microcrystalline cellulose, and, optionally, additional excipients, in a solid dosage form.
[0021] Further, the present invention relates to a method of preparing an oral dosage form of a pharmaceutically active ingredient comprising dry blending the pharmaceutically active ingredient and at least about 50 weight % of the B-sheet form of microcrystalline cellulose, and compressing the blend to form a solid dosage.
Brief Description of Drawings [0022] Figure 1 illustrates various solid dosage forms such as cylindrical tablets and raised violin shaped tablets;
Brief Description of Drawings [0022] Figure 1 illustrates various solid dosage forms such as cylindrical tablets and raised violin shaped tablets;
[0023] Figure 2 illustrates a Manesty tableting machine;
[0024] Figure 3 illustrates a tableting die pair;
[0025] Exhibit A indicates testing of tableting machines.
[0026] Exhibit B illustrates stability testing of various solid dosage formulations.
Detailed Description [0027] The present invention is a pharmaceutical product that is in the form of a solid dosage, such as a sublingual lozenge, buccal tablet, oral lozenge, suppository or a compressed tablet. The pharmaceutically active ingredient is dry mixed with the B-sheet form of the microcrystalline cellulose, optionally with additional excipients, and formed into a suitable solid dosage.
Detailed Description [0027] The present invention is a pharmaceutical product that is in the form of a solid dosage, such as a sublingual lozenge, buccal tablet, oral lozenge, suppository or a compressed tablet. The pharmaceutically active ingredient is dry mixed with the B-sheet form of the microcrystalline cellulose, optionally with additional excipients, and formed into a suitable solid dosage.
(0028] The present invention can be prepared as a direct compression formula, dry granulation formula, or as a wet granulation formula, with or without preblending of the drug, although preferably with preblending.
(0029] The pharmaceutically active ingredient can be any type of medication which acts locally in the mouth or systemically, which is the case of the latter, can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood, fluids and tissues of the body, Alternatively, the medicament can be of any type of medication which acts through the buccal tissues of the mouth to transmit the active ingredient directly into the blood stream thus avoiding first liver metabolism and by the gastric and intestinal fluids which often have an adverse inactivating or destructive action on many active ingredients unless they are specially protected against such fluids as by means of an enteric coating or the like. The active ingredient can also be of a type of medication which can be transmitted into the blood circulation through the rectal tissues.
[0030] Representative active medicaments include antacids, antisubstances, coronary dilators, peripheral vasodilators, antipsychotropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrosedatives, antidiarrheal preparations, antidrugs, vasodilators, antiarrythmics, antidrugs, vasoconstrictors and migraine treatments, anticoagulants and antithrombiotic drugs, analgesics, antihypnotics, sedatives, antiantianticonvuisants, neuromuscular drugs, hyper and hypoglycaemic agents, thyroid and antithyroid preparations, diuretics, antispasmodics, uterine relaxants, mineral and nutritional additives, antiobesity drugs, anabolic drugs, erthropoietic drugs, antiasthematics, expectorants, cough suppressants, mucolytics, antiuricemic drugs, and drugs or substances acting locally in the mouth.
[0031 ] Typical active medicaments include gastrointestinal sedatives such as metoclopramide and propantheline bromide, antacids such as aluminum trisilicate, aluminum hydroxide and cimetidine, antidrugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prenisone and prednisolone, coronary vasodialator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate, peripheral and cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, comesylate, cyclandelate, papaverine and nicotinic acid, antisubstances such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucolaxacillin sodium, hexamine mandelate and hexamine hippurate, neuroleptic drugs such as fluazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine, central nervous stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride, antidrugs such as diphenhydramine, diphenylpyraline, chlorplieniramine and brompheniramine, antidiarrheal drugs such as bisacodyl and magnesium hydroxide, the laxative drug, dioctyl sodium sulfosuccinate, nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine and pyridoxine, antidrugs such as dicyclomine and diphenoxylate, drugs effecting the rhythm of the heart such as verapamil, nifedepine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate, drugs used in the treatment of hypertension such as propranolol hydrochloride, guanethidine monosulphante, methyldopa, oxprenolol hydrochloride, captopril and hydralazine, drugs used in the treatment of migraine such as ergotamine, drugs effecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate, analgesic drugs such as acetylsalicyclic acid9 acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxydodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid, antidrugs such as phenytoin sodium and sodium valproate, neuromuscular drugs such as dantrolene sodium, substances used in the treatment of diabetes, such as tolbutamide, diabenase glucagon and insulin, drugs used in the treatment of thyroid gland dysfunction such as triiodothyronine, liothyronine sodium, levothyroxine sodium and propylthiouracil, diuretic drugs, such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone and triampterene, the uterine relaxant drugr itodrine; appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride, antidrugs such as aminophylline, theophylline, salbutamol, orciprenaline sulphate and terbutaline sulphate, expectorant drug such as guaiphenesin, cough suppressants such as dextromethorphan and noscapine, mucolytic drugs such as carbocisteine, antiseptics such as cetylpyridinium chloride, tyrothricin and chlorhexidine, decongestant drugs such as phenylpropanolamine and pseudoephedrine, hypnotic drugs such as dichloralphenazone and nitrazepam, antidrugs such as promethazine theoclate, haemopoetic drugs such as ferrous sulphate, folic acid and calcium gluconate, uricosuric drugs such as sulphinpyrazine, allopurinol and probenecid and the like. It is understood that the invention is not restricted to the above medications.
[0032] The amount of pharmaceutically active ingredient in the present composition can vary widely, as desired, Preferably, the active ingredient is present In the composition in the range of about 0.001 to about 10 weight %. More preferably, the amount of active ingredient is present in the range of about 0.001 to 5 weight %.
[0033] When the pharmaceutically active moiety is levothyroxine sodium or liothyronine sodium, the preferred amount of the active moiety in the composition is in the range of about 0.01 to 5 weight %. The more preferred rmge is from about 0.01 to 10 weight levothyroxine. The minimum amount of levothyroxine can vary, so long as an effective amount is utilized to cause the desired pharmacological effect, Typically, the dosage forms have a content of levothyroxine in the range of about 25 to 300 micrograms.
[0034] "The B-sheet microcrystalline cellulose product of the present Invention is prepared by forming a wet cake, drying the cake with a drum dryer, then passing the dried product through a screen or mill for sizing which produces a B-sheet microcrystalline cellulose which has a flat needle shape, as disclosed in U.S. Patent 5,574,150. Said B-sheet microcrystalline product can be prepared by Asahi Chemical of Japan and marketed by FMC Company of Newark, Del, under the trademark CEOLUS. The morphology and performance characteristics of the Ceolus product are different From those of other a-form microcellulose products (for example, Avicel and Emcocel), and arc suitable for preparing the present stabilized pharmaceutical composition.
[0035] The amount of a B-sheet microcrystalline product used in the present composition is at least 50 weight % of the final composition. Preferably, the amount of B-sheet microcrystalline product is in the range of about 50 to 99 weight %. Most preferably, the amount of B-sheet microcrystalline product is in the range of about 6.0 to 90 weight % of the final composition.
[0036] Other suitable excipients for the present invention include fillers such as starch, alkaline inorganic salts such as trisodium phosphate, tricalcium phosphate, calcium sulfate and sodium or magnesium carbonate, The fillers can be present in the present composition in the range of about 0 to 50 weight %.
[0037] Suitable disintegrating agents include corn starch, cross-linked sodium carboxymethylcellulose (croscarmellose) and cross-linked polyvinylpymolidone (crospovidone). A preferred disintegrating agent is croscarmellose. The amount of disintegrating agent used is in the range of about 0 to 50 weight %.
Preferably, the disintegrating agent is in the range of about 10 to 40 weight %.
[0038] Suitable glidents for use in the present invention include colloidal silicon dioxide and talc. The amount of glident in the present composition is from about 0 to 5 weight %, and the preferred amount is about 0 to 2 weight %.
[0039] Suitable lubricants include magnesium and zinc stearate, sodium stearate fumarate and sodium and magnesium lauryl sulfate. A preferred lubricant is magnesium stearate, The amount of lubricant is typically in the range of about 0 to 5 weight %, preferably in the range of about 0.1 to 3 weight %.
[0040] The oral pharmaceutical product is prepared by thoroughly intermixing the active moiety and the B-sheet form of microcrystalline cellulose, along with other excipients to form the oral dosage. Food grade dyes can also be added. For example, it is common to distinguish dosages of various potency by the color characteristics of such dyes.
j0041 ] The stabilized oral dosages of thyroid hormone are prepared by forming a trituration of the active moiety (i.e. levothyroxine sodium and/or liothyronine sodium) and B-sheet microcrystalline cellulose. The trituration is blended with B-sheet microcrystalline cellulose and additional excipients and compressed into oral dosages.
[0042] Design of the tableting apparatus is critical to maintain consistency from one oral dosage to the next. The formulation batches are a blend of solid compositions of various shapes and sizes. Blending is used to achieve a measure of homogeneity. In particular the active thyroid moiety is desired to be evenly distributed throughout the batch, In a typical 400 kg batch, the amount of active moiety represents less than 1 kg of the total weight, For example, when producing 145 mg tablets with a 300 mcg dosage, approximately 0.8 kg of a 400 kg batch is the active moiety. In addition each tablet is to contain from 100% to 102.5% label claim potency (higher dosage levels may use a narrower 100% to tolerance).
[0043] It is typical for compressible medicament tablets to be formed using a 2:1 fill to compression ratio. However, for medicamet tablets formed using the present invention a fill to compression ratio from 3.3:1 to A:1 is needed to obtain desired tablet density. This results from the B-sheet microcrystalline cellulose having a lower bulk density, as compared to other excipients, [0044] Higher tablet density can be accomplished by adjusting a tableting machine to increase the compression ratio. Tableting machines are commonly known to practitioners in the art and include those available from Manesty and Stokes. It has been found that making such adjustments to the compression ratio results in poor tablet surface finish as well as inconsistent tablet weights.
[0045] Instead, the design of the tableting dies must be adjusted, It has been determined that during the filling of the tableting dies, a minimum of 5-6 mm die overfill. In most cases this requires replacement of the tableting dies with dies an additional 2-3 mm deep.
[0046] When using the extra-deep dies and a compression ratio of from 3.3:1 to 4.0:1 consistent weight tablets with good surface finish were produced.
[0047] EXAMPLES
[0048] Stability testing was performed on samples of the thyroid hormone drug formulation used in manufacturing tablets with an active moiety of levothyroxine sodium, Tests were performed on direct compression formulations for dosage strength of 25 mcg.
Example 1 tablets eompnise the B-sheet microcrystalline cellulose while Control 1 tablets comprise the traditional a-form microcrystalline cellulose. The composition of Example I and Control 1 tablets are presented in Table 1 and stability test results In Table 2:
[0049]
(t3]
Table I Tablet Formulation for ZS mcg Dosages of Levothyroxine Sodium Example 1 Table Control 1 Component Tablet 0.0297 0.0297 mg Levothyroxine Sodium, USP
mg 108.55 mg B-sheet microcrystalline cellulose 108.55 x - form microcrystalline cellulose mg 35.079 35.079 mg Croscarmellose Sodium, NF
mg 0.352 0.352 mg FD&C Yellow #6 16% (14-20%
mg 1.018 1.018 mg Magnesium Stearate, NF
mg 145.0 mg total [0050]
Table 2 - Stability Test - Potency at 25° C - % Label Claim Elapsed Time 0 73 Days 13 Months 15 Months Example 1 Table 106.4 105.5 104.4 102.9 Example I % Potency 0.9 % 2.0 % 3.5 Loss Control 1 Tablet 99.2 89.5 85.0 83.2 Control a % Potency ~ ~ 2.7 % ~ 14.2 % I 16.0 Loss ~
[0051) As seen in Table 2, the stability of pharmaceutical formulations of the present invention are improved significantly by the use of the B-sheet microcrystalline cellulose. Potency loss of the present invention is 3.5% versus 16.0% potency loss experienced in a similar formulatio with the a-form microcrystalline cellulose.
[0052] Tableting testing was performed on the formulation for Example 1 tablets. Initial results with standard die depths was a relative standard deviation of 2.2 to 3,5%
tablet weight.
With the use of the herein described extra deep tablet dies, the relative standard deviation is 1.2%. Testing was performed on a Manesty tableting machine with compression ratios offrom3.3:1 t04.0:1.
[0053] Tablet quality is also dependent upon the storage of the B-sheet microcrystalline cellulose. Best results are achieved when the cellulose i5 received in drums or portable containers instead of bags. The bag form suffers from compression during transportation from raw material suppliers. Test results for tableting are presented in attached Exhibit A.
[0054] Additional examples of solid dosage formulations are illustrated in Tables 3 and 4, Stability testing data of these additional examples are illustrated in attached Exhibit B.
[0055]
Table 3 - Tablet Formulation for Dosages of Levothyroxine Sodium 25 mcg 50 mcg 75 mcg Component Dosage Dosage Dosage 9.925 0.0500 0.0750 Levothyroxine sodium mg/tablet mg/tablet mg/tablet 108.529 108.55b 108.438 B-Sheet microcrystalline mg/tablet mg/tablet mg/tablet Cellulose 35.079 35.079 35.079 crosscarmellose sodium mg/tablet mg/tablet mg/tablet 0.352 0.383 Food Grade Dye mg/tablet mg/tablet 1.018 1.018 1.018 magnesium stearate mg/tablet mg/tablet mg/tablet 145 mg/tablet145 mg/tablet 145 mg/tablet total [0056]
Table Q - Tablet Formulation for Dosages of Levothyroxine Sodium 100 mcg 112 mcg 300 mcg Component Dosage Dosage Dosage 0.100 0.112 0.300 levothyroxine sodium mg/tablet mg/tablet mg/tablet 108.406 107.711 108.451 B-sheet microcrystalline mg/tablet mg/tablet mg/tablet cellulose 35.079 35.079 35.079 crosscarmellose sodium mg/tablet mg/tablet mg/tablet 0.388 1.080 0.142 Food Grade Dye mg/tablet mg/tablet mg/tablet 1.018 1.018 1.1018 magnesium stearate mg/tablet mg/tablet mg/tablet 145 mg/tablet145 mgltablet 145 mg/tablet Total [0057] While the present invention ha been described in the context of preferred embodiments and examples, it will be readily apparent to those skilled in the art that ether modifications and variations can be made therein without departing from the spirit or scope of the present invention. For example, the active moiety levothyroxine sodium can be changed to liothyronine sodium and similar products and still be considered as part of the claimed invention. Accordingly, it is not intended that the present invention be limited to the specifics of the foregoing description of the preferred embodiments arid examples, but rather as being limited only by the scope of the invention as defined in the claims appended hereto.
[0031 ] Typical active medicaments include gastrointestinal sedatives such as metoclopramide and propantheline bromide, antacids such as aluminum trisilicate, aluminum hydroxide and cimetidine, antidrugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prenisone and prednisolone, coronary vasodialator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate, peripheral and cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, comesylate, cyclandelate, papaverine and nicotinic acid, antisubstances such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucolaxacillin sodium, hexamine mandelate and hexamine hippurate, neuroleptic drugs such as fluazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine, central nervous stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride, antidrugs such as diphenhydramine, diphenylpyraline, chlorplieniramine and brompheniramine, antidiarrheal drugs such as bisacodyl and magnesium hydroxide, the laxative drug, dioctyl sodium sulfosuccinate, nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine and pyridoxine, antidrugs such as dicyclomine and diphenoxylate, drugs effecting the rhythm of the heart such as verapamil, nifedepine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate, drugs used in the treatment of hypertension such as propranolol hydrochloride, guanethidine monosulphante, methyldopa, oxprenolol hydrochloride, captopril and hydralazine, drugs used in the treatment of migraine such as ergotamine, drugs effecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate, analgesic drugs such as acetylsalicyclic acid9 acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxydodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid, antidrugs such as phenytoin sodium and sodium valproate, neuromuscular drugs such as dantrolene sodium, substances used in the treatment of diabetes, such as tolbutamide, diabenase glucagon and insulin, drugs used in the treatment of thyroid gland dysfunction such as triiodothyronine, liothyronine sodium, levothyroxine sodium and propylthiouracil, diuretic drugs, such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone and triampterene, the uterine relaxant drugr itodrine; appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride, antidrugs such as aminophylline, theophylline, salbutamol, orciprenaline sulphate and terbutaline sulphate, expectorant drug such as guaiphenesin, cough suppressants such as dextromethorphan and noscapine, mucolytic drugs such as carbocisteine, antiseptics such as cetylpyridinium chloride, tyrothricin and chlorhexidine, decongestant drugs such as phenylpropanolamine and pseudoephedrine, hypnotic drugs such as dichloralphenazone and nitrazepam, antidrugs such as promethazine theoclate, haemopoetic drugs such as ferrous sulphate, folic acid and calcium gluconate, uricosuric drugs such as sulphinpyrazine, allopurinol and probenecid and the like. It is understood that the invention is not restricted to the above medications.
[0032] The amount of pharmaceutically active ingredient in the present composition can vary widely, as desired, Preferably, the active ingredient is present In the composition in the range of about 0.001 to about 10 weight %. More preferably, the amount of active ingredient is present in the range of about 0.001 to 5 weight %.
[0033] When the pharmaceutically active moiety is levothyroxine sodium or liothyronine sodium, the preferred amount of the active moiety in the composition is in the range of about 0.01 to 5 weight %. The more preferred rmge is from about 0.01 to 10 weight levothyroxine. The minimum amount of levothyroxine can vary, so long as an effective amount is utilized to cause the desired pharmacological effect, Typically, the dosage forms have a content of levothyroxine in the range of about 25 to 300 micrograms.
[0034] "The B-sheet microcrystalline cellulose product of the present Invention is prepared by forming a wet cake, drying the cake with a drum dryer, then passing the dried product through a screen or mill for sizing which produces a B-sheet microcrystalline cellulose which has a flat needle shape, as disclosed in U.S. Patent 5,574,150. Said B-sheet microcrystalline product can be prepared by Asahi Chemical of Japan and marketed by FMC Company of Newark, Del, under the trademark CEOLUS. The morphology and performance characteristics of the Ceolus product are different From those of other a-form microcellulose products (for example, Avicel and Emcocel), and arc suitable for preparing the present stabilized pharmaceutical composition.
[0035] The amount of a B-sheet microcrystalline product used in the present composition is at least 50 weight % of the final composition. Preferably, the amount of B-sheet microcrystalline product is in the range of about 50 to 99 weight %. Most preferably, the amount of B-sheet microcrystalline product is in the range of about 6.0 to 90 weight % of the final composition.
[0036] Other suitable excipients for the present invention include fillers such as starch, alkaline inorganic salts such as trisodium phosphate, tricalcium phosphate, calcium sulfate and sodium or magnesium carbonate, The fillers can be present in the present composition in the range of about 0 to 50 weight %.
[0037] Suitable disintegrating agents include corn starch, cross-linked sodium carboxymethylcellulose (croscarmellose) and cross-linked polyvinylpymolidone (crospovidone). A preferred disintegrating agent is croscarmellose. The amount of disintegrating agent used is in the range of about 0 to 50 weight %.
Preferably, the disintegrating agent is in the range of about 10 to 40 weight %.
[0038] Suitable glidents for use in the present invention include colloidal silicon dioxide and talc. The amount of glident in the present composition is from about 0 to 5 weight %, and the preferred amount is about 0 to 2 weight %.
[0039] Suitable lubricants include magnesium and zinc stearate, sodium stearate fumarate and sodium and magnesium lauryl sulfate. A preferred lubricant is magnesium stearate, The amount of lubricant is typically in the range of about 0 to 5 weight %, preferably in the range of about 0.1 to 3 weight %.
[0040] The oral pharmaceutical product is prepared by thoroughly intermixing the active moiety and the B-sheet form of microcrystalline cellulose, along with other excipients to form the oral dosage. Food grade dyes can also be added. For example, it is common to distinguish dosages of various potency by the color characteristics of such dyes.
j0041 ] The stabilized oral dosages of thyroid hormone are prepared by forming a trituration of the active moiety (i.e. levothyroxine sodium and/or liothyronine sodium) and B-sheet microcrystalline cellulose. The trituration is blended with B-sheet microcrystalline cellulose and additional excipients and compressed into oral dosages.
[0042] Design of the tableting apparatus is critical to maintain consistency from one oral dosage to the next. The formulation batches are a blend of solid compositions of various shapes and sizes. Blending is used to achieve a measure of homogeneity. In particular the active thyroid moiety is desired to be evenly distributed throughout the batch, In a typical 400 kg batch, the amount of active moiety represents less than 1 kg of the total weight, For example, when producing 145 mg tablets with a 300 mcg dosage, approximately 0.8 kg of a 400 kg batch is the active moiety. In addition each tablet is to contain from 100% to 102.5% label claim potency (higher dosage levels may use a narrower 100% to tolerance).
[0043] It is typical for compressible medicament tablets to be formed using a 2:1 fill to compression ratio. However, for medicamet tablets formed using the present invention a fill to compression ratio from 3.3:1 to A:1 is needed to obtain desired tablet density. This results from the B-sheet microcrystalline cellulose having a lower bulk density, as compared to other excipients, [0044] Higher tablet density can be accomplished by adjusting a tableting machine to increase the compression ratio. Tableting machines are commonly known to practitioners in the art and include those available from Manesty and Stokes. It has been found that making such adjustments to the compression ratio results in poor tablet surface finish as well as inconsistent tablet weights.
[0045] Instead, the design of the tableting dies must be adjusted, It has been determined that during the filling of the tableting dies, a minimum of 5-6 mm die overfill. In most cases this requires replacement of the tableting dies with dies an additional 2-3 mm deep.
[0046] When using the extra-deep dies and a compression ratio of from 3.3:1 to 4.0:1 consistent weight tablets with good surface finish were produced.
[0047] EXAMPLES
[0048] Stability testing was performed on samples of the thyroid hormone drug formulation used in manufacturing tablets with an active moiety of levothyroxine sodium, Tests were performed on direct compression formulations for dosage strength of 25 mcg.
Example 1 tablets eompnise the B-sheet microcrystalline cellulose while Control 1 tablets comprise the traditional a-form microcrystalline cellulose. The composition of Example I and Control 1 tablets are presented in Table 1 and stability test results In Table 2:
[0049]
(t3]
Table I Tablet Formulation for ZS mcg Dosages of Levothyroxine Sodium Example 1 Table Control 1 Component Tablet 0.0297 0.0297 mg Levothyroxine Sodium, USP
mg 108.55 mg B-sheet microcrystalline cellulose 108.55 x - form microcrystalline cellulose mg 35.079 35.079 mg Croscarmellose Sodium, NF
mg 0.352 0.352 mg FD&C Yellow #6 16% (14-20%
mg 1.018 1.018 mg Magnesium Stearate, NF
mg 145.0 mg total [0050]
Table 2 - Stability Test - Potency at 25° C - % Label Claim Elapsed Time 0 73 Days 13 Months 15 Months Example 1 Table 106.4 105.5 104.4 102.9 Example I % Potency 0.9 % 2.0 % 3.5 Loss Control 1 Tablet 99.2 89.5 85.0 83.2 Control a % Potency ~ ~ 2.7 % ~ 14.2 % I 16.0 Loss ~
[0051) As seen in Table 2, the stability of pharmaceutical formulations of the present invention are improved significantly by the use of the B-sheet microcrystalline cellulose. Potency loss of the present invention is 3.5% versus 16.0% potency loss experienced in a similar formulatio with the a-form microcrystalline cellulose.
[0052] Tableting testing was performed on the formulation for Example 1 tablets. Initial results with standard die depths was a relative standard deviation of 2.2 to 3,5%
tablet weight.
With the use of the herein described extra deep tablet dies, the relative standard deviation is 1.2%. Testing was performed on a Manesty tableting machine with compression ratios offrom3.3:1 t04.0:1.
[0053] Tablet quality is also dependent upon the storage of the B-sheet microcrystalline cellulose. Best results are achieved when the cellulose i5 received in drums or portable containers instead of bags. The bag form suffers from compression during transportation from raw material suppliers. Test results for tableting are presented in attached Exhibit A.
[0054] Additional examples of solid dosage formulations are illustrated in Tables 3 and 4, Stability testing data of these additional examples are illustrated in attached Exhibit B.
[0055]
Table 3 - Tablet Formulation for Dosages of Levothyroxine Sodium 25 mcg 50 mcg 75 mcg Component Dosage Dosage Dosage 9.925 0.0500 0.0750 Levothyroxine sodium mg/tablet mg/tablet mg/tablet 108.529 108.55b 108.438 B-Sheet microcrystalline mg/tablet mg/tablet mg/tablet Cellulose 35.079 35.079 35.079 crosscarmellose sodium mg/tablet mg/tablet mg/tablet 0.352 0.383 Food Grade Dye mg/tablet mg/tablet 1.018 1.018 1.018 magnesium stearate mg/tablet mg/tablet mg/tablet 145 mg/tablet145 mg/tablet 145 mg/tablet total [0056]
Table Q - Tablet Formulation for Dosages of Levothyroxine Sodium 100 mcg 112 mcg 300 mcg Component Dosage Dosage Dosage 0.100 0.112 0.300 levothyroxine sodium mg/tablet mg/tablet mg/tablet 108.406 107.711 108.451 B-sheet microcrystalline mg/tablet mg/tablet mg/tablet cellulose 35.079 35.079 35.079 crosscarmellose sodium mg/tablet mg/tablet mg/tablet 0.388 1.080 0.142 Food Grade Dye mg/tablet mg/tablet mg/tablet 1.018 1.018 1.1018 magnesium stearate mg/tablet mg/tablet mg/tablet 145 mg/tablet145 mgltablet 145 mg/tablet Total [0057] While the present invention ha been described in the context of preferred embodiments and examples, it will be readily apparent to those skilled in the art that ether modifications and variations can be made therein without departing from the spirit or scope of the present invention. For example, the active moiety levothyroxine sodium can be changed to liothyronine sodium and similar products and still be considered as part of the claimed invention. Accordingly, it is not intended that the present invention be limited to the specifics of the foregoing description of the preferred embodiments arid examples, but rather as being limited only by the scope of the invention as defined in the claims appended hereto.
Claims (3)
-
- Claims [c1] A pharmaceutical composition in solid form comprising a pharmaceutically active ingredient and a B-sheet form of microcrystalline cellulose.
[c2] The pharmaceutical composition of claim [c1] [Claim Reference] wherein at least about 50n weight % of the composition weight B-sheet form of microcrystalline cellulose.
[c3] The pharmaceutical composition of claim [c1] [Claim Reference) wherein the active ingredient is levothyroxine sodium [c4] The pharmaceutical composition of claim [c2) [Claim Reference] wherein the active ingredient is levothyroxine sodium.
[c5] The pharmaceutical composition of claim [c1] [Claim Reference] wherein the active ingredient is liothyronine sodium, [c6] The pharmaceutical composition of claim [c2] [Claim Reference] wherein the active ingredient is liothyronine sodium.
[c7] A method of preparing a solid dosage form of a pharmaceutically active ingredient comprising forming a blend by blending the pharmaceutically active ingredient and B-sheet form of microcrystalline cellulose, and forming therefrom a solid dosage.
[c8] The method of claim [c7] [Claim Reference] wherein the solid dosage is formed by compressing the blend in a tableting machine.
[c9] The method of claim [c8] [Claim Reference] wherein the blend is compressed in a ratio of initial volume to final volume from 3.3:1 to 4.0:1.
[c 10] The method of claim [c7] [Claim Reference] wherein the pharmaceutically active ingredient comprises levothyroxine sodium.
[c11] The method of claim [c7] [Claim. Reference] wherein the pharmaceutically active ingredient comprises liothyronine sodium [c 12] The method of claim [c8] [Claim Reference] wherein the tableting machine further comprises extra deep tablet dies that maintain a free clearance of at least - 3.0 mm during filling.
[c13] The method of claim [c12) [Claim Reference] wherein the tableting machine forms tablets in a shape selected from the group consisting of cylindrical shape and raised violin shape.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26900901P | 2001-02-15 | 2001-02-15 | |
US60/269,009 | 2001-02-15 | ||
PCT/US2002/004664 WO2002064093A2 (en) | 2001-02-15 | 2002-02-15 | Stabilized pharmaceutical and thyroid hormone compositions and method of preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2438641A1 true CA2438641A1 (en) | 2002-08-22 |
Family
ID=23025455
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002438641A Abandoned CA2438641A1 (en) | 2001-02-15 | 2002-02-15 | Stabilized pharmaceutical and thyroid hormone compositions and method of preparation |
Country Status (9)
Country | Link |
---|---|
US (1) | US7067148B2 (en) |
EP (1) | EP1365745A2 (en) |
JP (1) | JP2004525109A (en) |
KR (1) | KR20040100835A (en) |
BR (1) | BR0207297A (en) |
CA (1) | CA2438641A1 (en) |
MX (1) | MXPA03007337A (en) |
NO (1) | NO20033637L (en) |
WO (1) | WO2002064093A2 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030099699A1 (en) * | 2001-11-13 | 2003-05-29 | Hanshew Dwight D. | Storage stable thyroxine active drug formulations and methods for their production |
US6645526B2 (en) * | 2001-11-13 | 2003-11-11 | Mylan Pharmaceuticals, Inc. | Storage stable thyroxine active drug formulations and methods for their production |
ITMI20110713A1 (en) | 2011-04-29 | 2012-10-30 | Bracco Imaging Spa | PROCESS FOR THE PREPARATION OF A SULFATE DERIVATIVE DI3,5-DIIODO-O- [3-IODOFENIL] -L-TIROSINA |
ITMI20022394A1 (en) | 2002-11-13 | 2004-05-14 | Bracco Spa | USE OF 3-SULPHATE TRIODOTHYRONIN AS A THYROIMIMETIC ACTIVITY AND RELATED PHARMACEUTICAL FORMULATIONS. |
DK1622587T3 (en) * | 2003-05-02 | 2010-08-23 | Globopharm Pharmazeutische Pro | Solid pharmaceutical preparation containing levothyroxine and / or liothyronine salts |
EP2019306A1 (en) * | 2007-07-24 | 2009-01-28 | Uhlmann VisioTec GmbH | System for manufacturing and testing tablets |
EP2932963A1 (en) | 2014-04-16 | 2015-10-21 | Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. | Stable pharmaceutical dosage forms comprising Levothyroxine sodium |
US9682045B2 (en) | 2014-11-21 | 2017-06-20 | Cadila Healthcare Limited | Stable pharmaceutical compositions of thyroid hormone drug |
US20170319526A1 (en) * | 2016-05-03 | 2017-11-09 | Spectrix Therapeutics, LLC | Compositions and methods of providing thyroid hormone or analogs thereof |
US10231931B1 (en) | 2018-03-23 | 2019-03-19 | Genus Lifesciences Inc. | Thyroid hormone oral dosage forms and methods of using the same |
Family Cites Families (116)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2642426A (en) | 1953-06-16 | Method of producing ihygopbotein | ||
US2436005A (en) | 1948-02-17 | Eleetrieal insulator anx method of | ||
US2426643A (en) | 1944-05-08 | 1947-09-02 | Norton Co | Method and apparatus for fusing refractory materials |
GB652207A (en) | 1948-12-31 | 1951-04-18 | Glaxo Lab Ltd | Improvements in or relating to the preparation of thyroxine and its derivatives |
US2705726A (en) | 1949-07-23 | 1955-04-05 | Sterling Drug Inc | Iodinated aminophenyl-carboxylic acids |
US2802869A (en) | 1952-12-08 | 1957-08-13 | Dow Chemical Co | Method of making cinnamic acid and salts thereof |
US2823164A (en) | 1953-02-25 | 1958-02-11 | Nat Res Dev | Method of preparing 3, 5, 3' l-tri-iodothyronine and pharmaceutical compositions thereof |
US2866738A (en) | 1955-01-12 | 1958-12-30 | American Cyanamid Co | Deionized corn steep liquor in production of tetracycline |
US2993928A (en) | 1957-01-15 | 1961-07-25 | Glaxo Lab Ltd | Preparation of triiodothyronine |
US3035974A (en) | 1960-02-18 | 1962-05-22 | Israel Murray | Compositions and method for the parenteral administration of thyroxine |
US3380818A (en) | 1964-03-18 | 1968-04-30 | Owens Illinois Inc | Glass composition and method and product |
US4110470A (en) | 1965-10-07 | 1978-08-29 | Horst Kummer | Pharmaceutical composition comprising d,l-α-methyl-thyroxine ethyl ester and the salts thereof and the control of cholesterol and triglyceride blood level therewith |
US3452599A (en) | 1966-12-22 | 1969-07-01 | Weston Instruments Inc | Temperature measuring devices |
US3808332A (en) | 1969-01-27 | 1974-04-30 | Armour Pharma | Pharmaceutical compositions containing the reaction product of a tertiary phosphine with thyroxine |
US3666854A (en) | 1969-07-30 | 1972-05-30 | Nuclear Med Lab | Test for thyroid hormone |
US3826767A (en) | 1972-01-26 | 1974-07-30 | Calgon Corp | Anionic dextran graft copolymers |
US4288546A (en) | 1976-04-09 | 1981-09-08 | The Regents Of The University Of Minnesota | Process for the large scale production of pituitary hormones by serial secondary suspension culture |
US4015939A (en) | 1976-05-12 | 1977-04-05 | Bio-Rad Laboratories, Inc. | Competitive binding thyroid assay with improved bound-free separation step |
US4115537A (en) | 1976-09-07 | 1978-09-19 | American Hospital Supply Corporation | Resin tablet and use thereof in diagnostic tests |
US4344934A (en) | 1978-11-20 | 1982-08-17 | American Home Products Corporation | Therapeutic compositions with enhanced bioavailability |
ZA817261B (en) | 1980-10-23 | 1982-09-29 | Schering Corp | Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them |
US4479947A (en) | 1981-07-13 | 1984-10-30 | Merck & Co., Inc. | Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group |
US4654331A (en) | 1981-07-13 | 1987-03-31 | Merck & Co., Inc. | Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group |
DE3226768A1 (en) | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF |
US4369172A (en) | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
US4539198A (en) | 1983-07-07 | 1985-09-03 | Rowell Laboratories, Inc. | Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range |
US4690824A (en) | 1983-07-07 | 1987-09-01 | Redi-Rowell, Inc. | Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range |
US4983392A (en) | 1983-11-14 | 1991-01-08 | Bio-Mimetics, Inc. | Bioadhesive compositions and methods of treatment therewith |
US5225196A (en) | 1983-11-14 | 1993-07-06 | Columbia Laboratories, Inc. | Bioadhesive compositions and methods of treatment therewith |
US4795436A (en) | 1983-11-14 | 1989-01-03 | Bio-Mimetics, Inc. | Bioadhesive composition and method of treatment therewith |
AU565354B2 (en) | 1983-11-14 | 1987-09-10 | Bio-Mimetics Inc. | Bioadhesive compositions and methods of treatment therewith |
CH658188A5 (en) | 1984-03-23 | 1986-10-31 | Ciba Geigy Ag | STORAGE STABLE QUICK DISASSEMBLING PHARMACEUTICAL PRESSELS. |
US4851228A (en) | 1984-06-20 | 1989-07-25 | Merck & Co., Inc. | Multiparticulate controlled porosity osmotic |
US4585652A (en) | 1984-11-19 | 1986-04-29 | Regents Of The University Of Minnesota | Electrochemical controlled release drug delivery system |
US4818531A (en) | 1985-02-06 | 1989-04-04 | Eli Lilly And Company | Growth hormone and thyroid hormone |
US4769319A (en) | 1985-05-31 | 1988-09-06 | Salk Institute Biotechnology Industrial Associates, Inc. | Nucleic acid probes for prenatal sexing |
IE63321B1 (en) | 1986-02-03 | 1995-04-05 | Elan Corp Plc | Drug delivery system |
JPS62210949A (en) | 1986-03-11 | 1987-09-17 | Kao Corp | Substitute cacao butter composition |
US4795644A (en) | 1987-08-03 | 1989-01-03 | Merck & Co., Inc. | Device for pH independent release of drugs through the Donnan-like influence of charged insoluble resins |
US4814183A (en) | 1987-08-31 | 1989-03-21 | Merck & Co., Inc. | Device for the controlled release of drugs with Donnan-like modulation by charged insoluble resins |
US4877774A (en) | 1987-09-09 | 1989-10-31 | The United States Of America As Represented By The Department Of Health And Human Services | Administration of steroid hormones |
US5244786A (en) | 1987-10-02 | 1993-09-14 | Microgenics Corporation | Method of measuring available free thyroxine bending sites |
US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US4980358A (en) | 1988-04-04 | 1990-12-25 | George D. McAdory | Method employing gonadal hormones and dopamine agonist intended for combined use in the improvement of lymphocyte function |
US5073555A (en) | 1988-04-04 | 1991-12-17 | George D. McAdory | Medicaments intended for combined use in the improvement of lymphocyte function to lower cholesterol levels |
US5064823A (en) | 1988-08-24 | 1991-11-12 | Research Triangle Institute | Pentacyclic triterpenoid compounds as topoisomerase inhibitors or cell differentiation inducers |
DE3830353A1 (en) | 1988-09-07 | 1990-03-15 | Basf Ag | METHOD FOR THE CONTINUOUS PRODUCTION OF SOLID PHARMACEUTICAL FORMS |
US5001115A (en) | 1989-05-17 | 1991-03-19 | University Of Florida | Prodrugs of biologically active hydroxyaromatic compounds |
US5767227A (en) | 1989-11-03 | 1998-06-16 | Lotus Biochemical Corp. | Iodothyronine polymers |
US5099001A (en) | 1989-12-28 | 1992-03-24 | Nepera, Inc. | Process for the production of thyroglobulin |
US5158978A (en) | 1990-02-05 | 1992-10-27 | British Technology Group (U.S.A.) | Thyroid hormone treatment of acute cardiovascular compromise |
US5989894A (en) | 1990-04-20 | 1999-11-23 | University Of Wyoming | Isolated DNA coding for spider silk protein, a replicable vector and a transformed cell containing the DNA |
US5686094A (en) | 1991-04-01 | 1997-11-11 | Theratech, Inc. | Controlled release formulations for the treatment of xerostomia |
US5176953A (en) | 1990-12-21 | 1993-01-05 | Amoco Corporation | Oriented polymeric microporous films |
US5412005A (en) | 1991-05-03 | 1995-05-02 | Novamont S.P.A. | Biodegradable polymeric compositions based on starch and thermoplastic polymers |
US5225204A (en) * | 1991-11-05 | 1993-07-06 | Chen Jivn Ren | Stable dosage of levothyroxine sodium and process of production |
EP0550108B1 (en) | 1991-12-30 | 1998-03-18 | Akzo Nobel N.V. | Sustained release thyroactive composition |
BR9305795A (en) | 1992-01-27 | 1997-02-18 | Univ North Carolina State | Gene transfer in birds by introducing dna into in ovo muscle |
US5310912A (en) | 1992-02-25 | 1994-05-10 | Research Biochemicals Limited Partnership | Iodinated neuroprobe for mapping monoamine reuptake sites |
US5698179A (en) | 1992-02-25 | 1997-12-16 | Neuro Imaging Technologies, Llc | Iodinated neuroprobe for mapping monoamine reuptake sites |
US5750089A (en) | 1996-01-11 | 1998-05-12 | Neuro Imaging Technologies, Llc | Halogenated neuroprobe for mapping monoamine reuptake sites |
US5461140A (en) | 1992-04-30 | 1995-10-24 | Pharmaceutical Delivery Systems | Bioerodible polymers for solid controlled release pharmaceutical compositions |
US5607691A (en) | 1992-06-12 | 1997-03-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
SG42869A1 (en) | 1992-08-05 | 1997-10-17 | Faulding F H & Co Ltd | Pelletised pharmaceutical composition |
US5811547A (en) | 1992-10-14 | 1998-09-22 | Nippon Shinyaju Co., Ltd. | Method for inducing crystalline state transition in medicinal substance |
WO1994009898A1 (en) | 1992-10-26 | 1994-05-11 | Schwarz Pharma Ag | Method of manufacturing microcapsules |
TW260612B (en) * | 1993-01-05 | 1995-10-21 | Asahi Chemical Ind | |
US5496934A (en) | 1993-04-14 | 1996-03-05 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Nucleic acids encoding a cellulose binding domain |
US5449522A (en) | 1993-08-24 | 1995-09-12 | Hill; Albert F. | Pharmaceutical composition for immunoenhancement therapy |
US5718969A (en) | 1993-08-25 | 1998-02-17 | Fmc Corporation | Nonaggregating hydrocolloid microparticulates, intermediates therefor, and processes for their preparation |
GB9401892D0 (en) * | 1994-02-01 | 1994-03-30 | Boots Co Plc | Therapeutic agents |
US5670380A (en) | 1994-05-04 | 1997-09-23 | Wu; Sing-Yung | Assay for fetal thyroid function |
US5618338A (en) | 1994-07-08 | 1997-04-08 | Canon Kabushiki Kaisha | Liquid composition, ink set and image-forming method and apparatus which employ the same |
US5910569A (en) | 1994-11-22 | 1999-06-08 | Lotus Biochemical Corporation | Iodothyronine polymers |
US6245350B1 (en) * | 1994-12-16 | 2001-06-12 | Warner-Lambert Company | Process for encapsulation of caplets in a capsule and solid dosage forms obtainable by such process |
PT797424E (en) | 1994-12-16 | 2000-10-31 | Warner Lambert Co | PROCESS FOR THE ENCAPSULATION OF "CAPLETS" IN A CAPSULE AND FORMS OF SOLID DOSAGE BY SUCH PROCESS |
US5888774A (en) | 1994-12-19 | 1999-03-30 | Cangene Corporation | Recombinant DNA molecules and expression vectors for erythropoietin |
DE4446470A1 (en) | 1994-12-23 | 1996-06-27 | Basf Ag | Process for the production of dividable tablets |
DE4446468A1 (en) | 1994-12-23 | 1996-06-27 | Basf Ag | Process for the production of coated tablets |
US6030613A (en) | 1995-01-17 | 2000-02-29 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
DE19504832A1 (en) | 1995-02-14 | 1996-08-22 | Basf Ag | Solid drug preparations |
DE19509806A1 (en) | 1995-03-21 | 1996-09-26 | Basf Ag | Storage stable dosage forms |
US6183596B1 (en) * | 1995-04-07 | 2001-02-06 | Tokushu Paper Mfg. Co., Ltd. | Super microfibrillated cellulose, process for producing the same, and coated paper and tinted paper using the same |
US6110909A (en) | 1995-09-13 | 2000-08-29 | Takeda Chemical Industries, Ltd. | Benzoxazepine compounds, their production and use as lipid lowering agents |
DE19536394A1 (en) * | 1995-09-29 | 1997-04-03 | Basf Ag | Solid pharmaceutical forms, obtainable by extrusion of a polymer-active substance melt containing isomalt |
DE19539361A1 (en) | 1995-10-23 | 1997-04-24 | Basf Ag | Process for the preparation of multilayer, solid pharmaceutical forms for oral or rectal administration |
DE19541128C2 (en) * | 1995-10-27 | 1997-11-27 | Henning Berlin Gmbh & Co | Stabilized thyroid hormone-containing medicines |
US5635209A (en) | 1995-10-31 | 1997-06-03 | Vintage Pharmaceuticals, Inc. | Stabilized composition of levothyroxine sodium medication and method for its production |
WO1997017951A1 (en) | 1995-11-14 | 1997-05-22 | Knoll Pharmaceutical Company | Stabilized thyroid hormone preparations and methods of making same |
HUT75956A (en) | 1995-11-29 | 1997-05-28 | Cyclolab | Pharmaceutical composition containing thyroxine |
DE19629753A1 (en) | 1996-07-23 | 1998-01-29 | Basf Ag | Process for the production of solid dosage forms |
US6261537B1 (en) * | 1996-10-28 | 2001-07-17 | Nycomed Imaging As | Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors |
EP0839526A3 (en) * | 1996-10-31 | 1999-01-07 | Takeda Chemical Industries, Ltd. | Solid pharmaceutical preparation with fast buccal disintegration or dissolution |
US6080383A (en) | 1997-01-13 | 2000-06-27 | Rose; Samuel | Method and composition for the treatment of cancer by the enzymatic conversion of soluble radioactive toxic agents into radioactive toxic precipitates in the cancer |
DE19710213A1 (en) | 1997-03-12 | 1998-09-17 | Basf Ag | Process for the manufacture of solid combination dosage forms |
AU6959898A (en) | 1997-04-11 | 1998-11-11 | David J. Grainger | Compounds and therapies for the prevention of vascular and non-vascular pathol ogies |
KR20010020432A (en) * | 1997-04-30 | 2001-03-15 | 토마스 씨. 서 | Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same |
US6046177A (en) | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
US5916910A (en) | 1997-06-04 | 1999-06-29 | Medinox, Inc. | Conjugates of dithiocarbamates with pharmacologically active agents and uses therefore |
EP0991699B1 (en) | 1997-06-18 | 2002-04-24 | Guilford Pharmaceuticals Inc. | Two-stage solution polymerization of high molecular weight poly(phosphoesters) |
US6028163A (en) | 1997-06-27 | 2000-02-22 | Guilford Pharmaceuticals Inc. | Solution polymerization of high molecular weight poly(phosphoesters) in toluene |
US6268197B1 (en) * | 1997-07-07 | 2001-07-31 | Novozymes A/S | Xyloglucan-specific alkaline xyloglucanase from bacillus |
US6221402B1 (en) * | 1997-11-20 | 2001-04-24 | Pfizer Inc. | Rapidly releasing and taste-masking pharmaceutical dosage form |
TW589174B (en) * | 1997-12-10 | 2004-06-01 | Takeda Chemical Industries Ltd | Agent for treating high-risk impaired glucose tolerance |
FR2772615B1 (en) * | 1997-12-23 | 2002-06-14 | Lipha | MULTILAYER TABLET FOR INSTANT RELEASE THEN PROLONGED ACTIVE SUBSTANCES |
US6190696B1 (en) * | 1998-06-08 | 2001-02-20 | Pieter J. Groenewoud | Stabilized thyroxine medications |
DE19830246A1 (en) * | 1998-07-07 | 2000-01-13 | Merck Patent Gmbh | Pharmaceutical preparation |
DE19840256A1 (en) * | 1998-09-03 | 2000-03-09 | Basf Ag | Widely applicable, continuous method for preparing coated solid dosage forms, comprises extruding mixture of drug and thermoplastic binder then applying coating composition in liquid or vapor form |
DE19847618A1 (en) * | 1998-10-15 | 2000-04-20 | Basf Ag | Production of solid dosage forms, used for e.g. pharmaceuticals or insecticides, by preparation of plastic mixture from polymeric binder and active agent under controlled conditions |
DE60012485T2 (en) * | 1999-02-18 | 2005-08-18 | The Regents Of The University Of California, Oakland | SALICYLAMIDE LANTHANIDE COMPLEXES FOR USE AS LUMINESCENCE MARKERS |
US6383471B1 (en) * | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
US6395300B1 (en) * | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
PH12000002657B1 (en) * | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
US6340471B1 (en) * | 1999-12-30 | 2002-01-22 | Alvin Kershman | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
US6399101B1 (en) * | 2000-03-30 | 2002-06-04 | Mova Pharmaceutical Corp. | Stable thyroid hormone preparations and method of making same |
US6555581B1 (en) * | 2001-02-15 | 2003-04-29 | Jones Pharma, Inc. | Levothyroxine compositions and methods |
-
2002
- 2002-02-15 EP EP02709558A patent/EP1365745A2/en not_active Withdrawn
- 2002-02-15 MX MXPA03007337A patent/MXPA03007337A/en not_active Application Discontinuation
- 2002-02-15 CA CA002438641A patent/CA2438641A1/en not_active Abandoned
- 2002-02-15 JP JP2002563890A patent/JP2004525109A/en active Pending
- 2002-02-15 KR KR10-2003-7010807A patent/KR20040100835A/en not_active Application Discontinuation
- 2002-02-15 US US10/076,999 patent/US7067148B2/en not_active Expired - Lifetime
- 2002-02-15 WO PCT/US2002/004664 patent/WO2002064093A2/en not_active Application Discontinuation
- 2002-02-15 BR BR0207297-1A patent/BR0207297A/en not_active IP Right Cessation
-
2003
- 2003-08-15 NO NO20033637A patent/NO20033637L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
JP2004525109A (en) | 2004-08-19 |
NO20033637D0 (en) | 2003-08-15 |
KR20040100835A (en) | 2004-12-02 |
US20030119911A1 (en) | 2003-06-26 |
EP1365745A2 (en) | 2003-12-03 |
WO2002064093A8 (en) | 2004-09-16 |
NO20033637L (en) | 2003-10-15 |
US7067148B2 (en) | 2006-06-27 |
BR0207297A (en) | 2005-04-19 |
MXPA03007337A (en) | 2005-03-07 |
WO2002064093A3 (en) | 2002-12-12 |
WO2002064093A2 (en) | 2002-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6555581B1 (en) | Levothyroxine compositions and methods | |
US20110071137A1 (en) | Process for preparing sustained release tablets | |
US7067148B2 (en) | Stabilized pharmaceutical and thyroid hormone compositions and method of preparation | |
US20080003284A1 (en) | Levothyroxine compositions and methos | |
US20030198668A1 (en) | Levothyroxine pharmaceutical compositions, methods of making and methods of administration | |
US7101569B2 (en) | Methods of administering levothyroxine pharmaceutical compositions | |
WO2003028624A2 (en) | Levothyroxine compositions and methods | |
WO2003070217A1 (en) | Levothyroxine compositions and methods | |
WO2004014318A2 (en) | Levothyroxine compositions and methods | |
WO2003013441A2 (en) | Levothyroxine compositions and methods | |
US20030194437A1 (en) | Levothyroxine compositions having unique triiodothyronine Cmax properties | |
US20030180353A1 (en) | Stabilized pharmaceutical compositions | |
US20030199585A1 (en) | Levothyroxine compositions and methods | |
US20040043066A1 (en) | Levothyroxine compositions having unique triiodothyronine Tmax properties | |
AU2002244037A1 (en) | Stabilized pharmaceutical and thyroid hormone compositions and method of preparation | |
US20030185885A1 (en) | Non-granulated levothyroxine pharmaceutical compositions | |
US20030198667A1 (en) | Methods of producing dispersible pharmaceutical compositions | |
US20030198672A1 (en) | Levothyroxine compositions having unique triidothyronine plasma AUC properties | |
US20030199588A1 (en) | Levothyroxine compositions and methods | |
US20030194436A1 (en) | Immediate release pharmaceutical compositions | |
US20030190349A1 (en) | Methods of stabilizing pharmaceutical compositions | |
US20030195254A1 (en) | Levothyroxine compositions having unique triiodothyronine Tmax properties | |
US20030199587A1 (en) | Levothyroxine compositions having unique Cmax properties | |
US20030199586A1 (en) | Unique levothyroxine aqueous materials | |
US20030203967A1 (en) | Levothyroxine compositions having unique Tmax properties |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |