HK1088543B - Pharmaceutical compositions and dosage forms of thalidomide - Google Patents

Description

Pharmaceutical compositions and dosage forms of thalidomide

This application claims priority to provisional application 60/426,016 filed on 11/14/2002, which is incorporated herein by reference in its entirety.

Technical Field

The invention relates, in part, to pharmaceutical compositions and dosage forms comprising thalidomide and pharmaceutically acceptable prodrugs, salts, solvates, hydrates, and clathrates thereof.

Background

Thalidomide is commercially available under the trade name THALOMIDThe racemic compound of (1), chemically named α - (N-phthalimido) glutarimide or 2- (2, 6-dioxo-3-piperidyl) -1H-isoindole-1, 3- (2H) -dione. Thalidomide was originally developed for the treatment of morning sickness in pregnant women, but was withdrawn from use due to a four-gene (tetragenic) effect. Thalidomide is currently approved in the united states for the treatment of erythema nodosum leprosum in humans. Physician's desktop reference1081-1085(55 th edition, 2001).

Thalidomide has been reported to have been used in patients with the following diseases: leprosy, Chronic graft-vs-host disease, rheumatoid arthritis, sarcoidosis, certain inflammatory skin diseases, and inflammatory bowel disease. See, generally, Koch, h.p., 22prog.med.chem.165-242 (1985). See also, Moiler, d.r. et al, 159j.immunol., 5157-5161 (1997); vasiliauskas, E.A. et al, 117Gastroenterology 1278-; and Ehrenpreis, E.D. et al, 117Gastroenterology 1271-. Patent US No.5,643,915 further states that thalidomide can be combined with other drugs to treat ischemia/reperfusion associated with coronary artery occlusion and brain occlusion.

In recent years, thalidomide has been used in the treatment of certain types of cancer. These cancers include refractory multiple myeloma, brain, melanoma, breast, colon, mesothelial, and renal cell carcinoma. See, for example, singhal, S. et al, 341(21) New England J Med., 1565-1571 (1999); and Marx, g.m. et al, 18proc.am. soc. clin. oncology, 454a (1999). It is further reported that thalidomide has been used to prevent the development of chronic cardiomyopathy in rats caused by doxorubicin. Costa p.t. et al, 92 (10: sup.1) Blood, 235b (1998). Other reports on the use of thalidomide for the treatment of certain cancers include the treatment of glioblastoma multiforme in combination with carboplatin. McCann J., DrugTopics 41-42(June 21, 1999). Thalidomide has also been reported as an antiemetic agent during treatment of astrocytomas. Zwart, D., 16(12) Aizneim-Forsch, 1688-. Methods for inhibiting angiogenesis are disclosed in U.S. patent 6,235,756B₁The disclosure of which is incorporated herein by reference in its entirety.

Thalidomide is administered orally to a patient. Thalidomide is administered orally in a No. 0 capsule containing 12.5% by weight of the composition relative to the total weight. The capsule fill weight was 400mg, and each capsule contained only 50mg of thalidomide. However, for the treatment of diseases such as cancer, a dose of 200-800mg is usually required. Thus, the patient may have to ingest 4-16 thalidomide capsules in order to obtain a therapeutically effective amount of the drug. Because the size of the size 0 capsule is large and large amounts of thalidomide are required to treat certain diseases and conditions, patient compliance can be an issue. In particular, some patients may not be able to receive thalidomide in the usual existing oral dosage forms, or ingest the large amounts of thalidomide necessary to effectively treat their disease. There is therefore a need for new pharmaceutical dosage forms of thalidomide.

Summary of The Invention

The invention encompasses novel pharmaceutical dosage forms of thalidomide and its pharmaceutically acceptable prodrugs, salts, solvates, hydrates, and clathrates. The invention further includes methods of using thalidomide and its pharmaceutically acceptable prodrugs, salts, solvates, hydrates, and clathrates in novel dosage forms for treating or preventing diseases and disorders such as, but not limited to, leprosy, chronic graft-versus-host disease, rheumatoid arthritis, sarcoidosis, inflammatory disorders, inflammatory bowel disease, and cancer.

Definition of

As used herein and unless otherwise stated, "substantially free" of a composition of compounds refers to a composition containing less than about 20 wt.%, preferably less than about 10 wt.%, more preferably less than about 5 wt.% and most preferably less than about 3 wt.% of compounds.

As used herein and unless otherwise stated, the term "stereomerically pure" refers to a composition that includes one stereoisomer of a compound but does not substantially include the other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center will contain substantially no antipodes of the compound. A stereomerically pure composition of a compound having two chiral centers will contain substantially no other non-corresponding isomers of the compound. Typical stereoisomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound; more preferably, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound; even more preferably, the compound comprises greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound; and most preferably comprises greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound.

As used herein and unless otherwise stated, the term "enantiomerically pure" refers to a stereomerically pure composition of a compound having one chiral center.

The term "pharmaceutically acceptable salt" as used herein includes, but is not limited to, salts of the acidic or basic moiety of thalidomide, unless otherwise specified. The basic moiety is capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used for the preparation of pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e. salts containing a pharmacologically acceptable anion. Suitable organic acids include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, acetic acid, formic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, oleic acid, tannic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, gluconic acid, glucaronicacid, saccharic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, or pamoic acid (i.e., 1, 1' -methylene-bis (2-hydroxy-3-naphthoic acid)). Suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid. Compounds including an amine moiety may form pharmaceutically acceptable salts with various amino acids other than the acids described above. The substantially acidic chemical moiety is capable of forming a base with various pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts, and, in particular, calcium, magnesium, sodium, lithium, zinc, potassium or iron salts.

As used herein to describe a compound moiety or chemical moiety, the term "derivative" refers to a compound moiety or chemical moiety in which the saturation of at least one bond has been changed (e.g., a single bond has been converted to a double or triple bond) or in which at least one hydrogen atom has been replaced by a different atom or chemical moiety. Examples of different atoms and chemical moieties include, but are not limited to, halogen, oxygen, nitrogen, sulfur, hydroxyl, methoxy, alkyl, amine, amide, ketone, and aldehyde.

As used herein and unless otherwise stated, the termThe term "prodrug" refers to a derivative of a compound that is hydrolyzed, oxidized, or otherwise reacted (in vitro or in vivo) under biological conditions to yield the compound. Examples of prodrugs include, but are not limited to, derivatives of thalidomide including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those containing-NO, -NO₂-ONO or-ONO₂Derivatives of part of thalidomide.

As used herein and unless otherwise stated, the terms "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to the carbamate, carbonate, ureide, or phosphate ester, respectively, of a compound: 1) does not interfere with the biological activity of the compound in vivo, but may impart advantageous properties to the compound, such as absorption, duration of action, or onset; or 2) are not biologically active, but are converted in vivo to biologically active compounds. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

As used herein and unless otherwise stated, the term "biohydrolyzable ester" refers to an ester of a compound: 1) does not interfere with the biological activity of the compound in vivo, but may impart advantageous properties to the compound, such as absorption, duration of action, or onset; or 2) are not biologically active, but are converted in vivo to biologically active compounds. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkylamidoalkyl esters, and choline esters.

As used herein and unless otherwise stated, the term "biohydrolyzable amide" refers to an amide of a compound: 1) does not interfere with the biological activity of the compound in vivo, but may impart advantageous properties to the compound, such as absorption, duration of action, or onset; or 2) are not biologically active, but are converted in vivo to biologically active compounds. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.

Detailed Description

The invention provides novel pharmaceutical dosage forms comprising thalidomide and pharmaceutically acceptable prodrugs, salts, solvates, hydrates, and clathrates thereof. Preferred dosage forms are suitable for oral administration to a patient. The preferred oral dosage form of thalidomide contains a higher weight percentage of thalidomide than the oral dosage forms of the drug of the prior art. The preferred oral dosage form of thalidomide is bioequivalent to, or has better bioavailability than, the currently approved oral dosage forms of the drug as approved by the U.S. food and drug administration.

The invention also includes kits comprising the pharmaceutical compositions and dosage forms of the invention. The invention also includes methods of treating and preventing diseases and disorders comprising administering to a patient in need thereof the pharmaceutical compositions and dosage forms of the invention.

For example, the invention encompasses single unit dosage forms suitable for oral administration to humans comprising greater than about 1, 5, 10, 15, 20, 25mg, or 30mg of the active ingredient; and an excipient; wherein the active ingredient is thalidomide or a pharmaceutically acceptable prodrug, salt, solvate, or clathrate thereof. Preferably, the amount of active ingredient is from about 5 to about 10% by weight, in which case the amount of active ingredient is from about 1 to about 5 mg.

Particular embodiments of the present invention include single unit dosage forms suitable for oral administration to humans comprising: greater than about 25mg of active ingredient; and an excipient; wherein the active ingredient is thalidomide or a pharmaceutically acceptable prodrug, salt, solvate, or clathrate thereof. Preferably, the amount of active ingredient is from about 30 to about 50% by weight, more preferably, about 40% by weight, in which case the amount of active ingredient is about 25mg or more.

A particular example of this embodiment is a single unit dosage form suitable for oral administration to a human, comprising: about 50mg of an active ingredient, wherein the active ingredient is thalidomide, or a pharmaceutically acceptable prodrug, salt, solvate, or clathrate thereof; about 74mg of a carrier, diluent or filler, wherein the carrier, diluent or filler comprises pregelatinized corn starch or microcrystalline cellulose or silicified microcrystalline cellulose or dicalcium phosphate; and about 1mg magnesium stearate; wherein the single unit dosage form is a size 4 capsule.

Another particular example includes a single unit dosage form suitable for oral administration to a human comprising: about 40% by weight of an active ingredient, wherein the active ingredient is thalidomide, or a pharmaceutically acceptable prodrug, salt, solvate, or clathrate thereof; about 53% by weight of a binder, wherein the binder comprises pregelatinized corn starch or microcrystalline cellulose; about 4% by weight of a surfactant; about 2% by weight of a disintegrant; and about 1 wt% of a lubricant; wherein the single unit dosage form is a tablet.

Another embodiment of the invention encompasses methods of treating or preventing leprosy, chronic graft versus host disease, rheumatoid arthritis, sarcoidosis, an inflammatory disease state, inflammatory bowel disease, or cancer, comprising administering to a patient in need of such treatment or prevention a single unit dosage form of the invention. In a preferred method, the disease is cancer.

The invention encompasses pharmaceutical compositions and single unit dosage forms of racemic and stereoisomerically pure thalidomide and pharmaceutically acceptable prodrugs, salts, solvates, hydrates, and clathrates thereof. Thalidomide is commercially available, but can also be prepared by methods known in the art. See, for example, The Merck Index, page 9182 (11 th edition, 1989) and references disclosed herein.

4.1.Pharmaceutical compositions and dosage forms

Pharmaceutical compositions and dosage forms of the invention contain a prophylactically or therapeutically effective amount of the active ingredient (i.e., thalidomide, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof) and an excipient. Preferred dosage forms are suitable for oral administration and may be coated to reduce or prevent degradation of the active ingredient in the gastrointestinal tract.

The pharmaceutical compositions and dosage forms of the invention may also contain one or more second active ingredients. Examples of the second active ingredient include, but are not limited to, anticancer drugs. Examples of anti-cancer drugs include, but are not limited to: acivicin, aclarubicin, alcorubicin hydrochloride, alclozoline, adolesin, aldesleukin, altretamine, ambroxycin, amenthraquinone acetate, aminoglutethimide, amsacrine, anastrozole, amtricin, asparaginase, clindamycin, azacitidine, azatepa, azomycin, batimastat, benzotepa, bicalutamide, bisantrene hydrochloride, bisnefaddyldimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bripirimid, busulfan, dactinomycin, caplastone, carbinamide, cabetim, carboplatin, carmustine hydrochloride, camaracin, casidarubicin, sildenafil, clofenamic acid, cilantro, cisplatin, cladribine, phoropterin, cyclophosphamide mesylate, cytarabine, dacarbazine, dactinomycin hydrochloride, cetrimide, dexomaplatin, dizaoguaning mesylate, diazaquinone, docetaxel, doxorubicin hydrochloride, droloxifene citrate, drotalandrone propionate, daptomycin, edatrexate, ilonithine hydrochloride, elsamitrucin, enloplatin, empprine, epipiperidine, epirubicin hydrochloride, ebuzole, esorubicin hydrochloride, estramustine sodium phosphate, etanidazole, etoposide phosphate, etolin, fadrozole hydrochloride, fazabine, fenviramide, azauridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquicin, fostricin sodium, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ifosfxin, interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2 a, interferon alpha-2 b, interferon alpha-n 1, interferon alpha-n 3, interferon beta-Ia, interferon gamma-Ib, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liazole hydrochloride, lometrexol sodium, lomustine, lossoxantrone hydrochloride, maxolone, maytansine (maytansine), mechlorethamine hydrochloride, megestrol acetate, melphalan, melnolium, mercaptopurine, methotrexate sodium, chlorpheniramine (metoprine), meltepa, mitodomide, mitocancin, mitocrycin, mitocrymin, mitocrylene, mitomycin, mitopersitemesine, mitoxantrone hydrochloride, mitoxantrone, mycophenolate, nocladamicin, doxoramycin, sumatriol, paclitaxel, platinum, paclitaxel, and platinum-2 b, nemustine, pelomomycin sulfate, pephosphoramide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, profestane, porfimer sodium, pofimycin, poitemustine, procarbazine hydrochloride, puromycin hydrochloride, pyrazolofuranin (pyrazofurin), lybodenosine, proglumide, safrog, safrol hydrochloride, semustine, octreozine, serpamidronate, spartamycin, germanium spiro ammonium hydrochloride, spiromustine, spiroplatinum, streptonigrin, streptozocin, sulfochlorpheniramine, talithromycin, ticalgaland sodium, tegafur, tilloanthraquinone hydrochloride, temoporfin, teniposide, tiruoximon, testolactone, thiamiprine, thioguanine, tipepidine, tiazepine, thiazoline, tirapamine, toremifene citrate, toremifene, trexolone acetate, trexate, tricirisone, tritozine, trimetrexate, triptorelin, tobrozole hydrochloride, uramustine, tolperispin, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinrosine sulfate, vinorelbine tartrate, vinrosine sulfate, vinzolidine sulfate, vorozole, zeniplatin, sethoxydim, and zorubicin hydrochloride. Other anticancer drugs include, but are not limited to: 20-epi-1, 25-dihydroxyvitamin D3, 5-acetyleneuropamidine, abiraterone, aclarubicin, acylfulvene, adecanenol, adolesleucin, aldesleukin (aidesleukin), ALL-TK antagonist, altretamine, ammustine, amidox, amifostine, aminolevulinic acid (aminolevulinic acid), amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitor, antagonist D, antagonist G, enriches (antarelix), anti-dorsalizing protein-1 (anti-dorsalmorphic protein-1), anti-hormonal substance, prostate cancer, anti-estrogenic drug, anti-malignant tumor substance, antisense nucleotide, glycine aphidicolin glycin (apoptosis), gene modulator, apoptosis regulator, purine nucleic acid (apurinic acid), adura-BA-PTba, arginine deaminase, asulamine, atamestan, amoxicillin, axinostatin 1, axinostatin 2, axinostatin 3, azasetron, azamycin (azatoxin), azatyrosine, baccatin III derivatives, balanol, batimastat, BCR/ABL antagonists, benzochlorins (benzochlorins), benzoylstaurosporine (benzoxystroburin), beta lactam derivatives, beta-alethine, beta-cloamyin B, betulinic acid (betacellinic acid), bFGF inhibitors, bicalutamide, bisabol, biziridinylspersmin, difaranide, cyclonexidine a (bistratane a), (bistratene a), bizelaine, efbronsted, bromopermine, budesonide, buthionine (buthionine), carboxin derivatives (carnitine, carboxin C-3, carboxin C-2, carboxin-2, carboxin derivatives, carbenexine, Casein kinase Inhibitor (ICOS), castanospermine (castanospermine), cecropin B, cetrorelix, chlorlins, chioroquinol sulfonamide, cicaprostil, cis-porphyrin, cladribine, clomiphene analogs, clotrimazole, glismicin A, glismicin B, pinocembrin A4, pinocembrin analogs, conagenin, crambescidin 816, camphanthol (crisnatol), cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentathraquinones, cyclopalatam, cyclopalmycin, cytarabine ocfosfate, cytolytic factors, Hexastipol (cytostatin), daclizumab, decitabine, dehydrogenine B, desloratadine B, dexamethasone, dexrazoxane, doxoramide, doxorazamide, doxorazine, doxoraline B, doxorazaline B, doxoraline, doxorazaline B (dihydropicloratadine, doxorazaline B), doxorazaline B, dolasetron, doxifluridine, droloxifene, dronabinol, duocarmycin SA, ebselen, etokomustine, edelfosine, eculizumab, eflornithine, elemene (elemene), ethimidefluoride, epirubicin, epristeride, estramustine analogs, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fazod, fazarabine, fenretinide, filgrastimide, finasteride, flavopiridol, fluzestine (flezelastine), fluasterone, fludarabine, fluorouroronicin hydrochloride, fophenicol, formestane, forskocin, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, galileosin, gelatinase inhibitor, gemcitabine, hypericin (hypericin), hypericum, diglucigenin (dihydroerucin), diglucidide (dihydroerubenamide), diglucidide (dihydroerubenacidamide), idoxifene, itomendone, imophoxin, ilomastat, imidazolacridone, imiquimod, immunostimulatory peptides, insulin-like growth factor-I receptor inhibitors, interferon antagonists, interferons, interleukins, iodobenzylguanidine, iododoxorubicin, Izodiol, 4-, iloplade, isogladine (irsogladine), isobengazole, isohomohalilone B, itasetron, jasplaolide, kahalalide F, lamelin-N-triacetate, lanreotide, leinadamycin, lewisetin, lentinan sulfate, leptin, letrozole, leukemia inhibitory factor, leukocyte interferon alpha, leuprolide + estrogen + progesterone, leuprolide, levamisole, linazole, linear polyamine analogs, lipophilic glycopeptides, platinum compounds, lissaminide, 7, lotropine, meglumine, luteolin, loxacin, lostatin, loxacin, lovastatin, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maytansine, mannostatin A, marimastat (marimastat), masolinol, maspin, matrix lytic factor (matrilysin) inhibitors, matrix metalloproteinase inhibitors, minolone, merbarone, metreleline, methionine, metoclopramide, MIF inhibitors, meprobinone, miltefosine, mitosin, mismatched double stranded RNA, mitoguazone, dibromodulcitol, mitomycin analogs, mitonaphthylamine, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofatin, moraxetin, monoclonal antibodies, human chorionic gonadotropin, monophosphoryl A + mycobacterial cell wall, mopidanol, multidrug resistance gene inhibitors, multiple tumor suppressor 1-based therapy, nitrogen mustard B, extract of Agrobacterium, acetyl mycobacterial, N-mycomycin, n-substituted benzamides, nafarelin, narcotine (nagristip), naloxone + pentazocine, napavin, naperpin, nartostatin, nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidants, carmustine, hexamethoxybenzyl guanine, octreotide, icekone, oligonucleotides, onapristone, ondansetron, oracin, oral cytokine inducers, ormaplatin, oxaliplatin, oxaauromicin, paclitaxel analogs, paclitaxel derivatives, palladium (palaamine), palmitoylrhizomycin (lmitoryloxxin), pamidronic acid, panaxatriol, paminofin, pramipetin, pezistine, penetron, pentosan, pentostatin, pazidine, pavoxyne, pavinol, pentostatin, or pentostatin, phosphatase inhibitors, streptolysin (pisibanil), pilocarpine hydrochloride, pirarubicin, pirtroxin, placetin A, placetin B, plasminogen activator inhibitors, platinum complexes, platinum-based compounds, platinum-triamine complexes, porfimer sodium, podofycin, prednisone, propylbisacridone, prostaglandin J2, proteasome inhibitors, protein A-series immunomodulators, protein kinase C inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurin, pyrazoacridine, pyridoxine hydroxylated hemoglobin polyoxyalkylene conjugates, raf antagonists, raltitrexendine, ramosetron, ras farnesyl protein transferase inhibitors, ras-GAP inhibitors, desmethyl rituxine (retept methylated), rhenium Re 186 sethionate, lisoproxiline, ribozymes, RII retinamide, ludwimine, rohitukin, romopeptide, roxiUquimec (roquinilex), rubiginone Bl, ruboxyl, safrog, saintopin, sarCNU, sarcophytol A, sarlamustine (sargramostim), Sdi 1 analogs, semustine, senescens derivative inhibitor 1, sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single chain antigen binding proteins, Sizoxazole, Sobusheng, sodium borocaacetate, sodium phenylacetate, solverol, somatomedin binding proteins, sonalamine, phosphinamine, phosphonoaspartic acid, spicamycin D, spiromustine, spongistatin1, squalamine (squamine), stem cell inhibitors, stem cell division inhibitors, stimide, matrixin inhibitors, finosine, vasoactive suramin, vasostatin, synthetic peptides, thazine, thaumatin iodide, tegafur, telluraprozynium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaalkoxide (tetrachlordecaoxide), tetrazoline, thiflustatin, thiocoraline (thiocoraline), thrombopoietin analogs, thymalfasin, thymopoietin receptor agonists, thymotreonam, thyroid stimulating hormone, tin ethyl protoporphyrin, tirapazamine, dichlorotitanium alkene, topsin, toremifene, tofipotent stem cell factor, translation inhibitors, retinoic acid, triacetyluridine, tricitabine, tritrexate, triptorelin, tropisetron, androurea, tyrosine kinase inhibitors, tyrosine phosphorylation inhibitors (tyrphostins), UBC inhibitors, umesatelomethazine, urogenital sinus derived growth inhibitory factor, urokinase receptor antagonists, pravastatin B, variolin B, therapeutic vectors, tretinomycin genes, tretinomycin, ryegrass, dinucleotides, verteporfin, vinorelbine, vinxaline, vitaxin, vorozole, zanoteron, zeniplatin, benzylidene, and netastatin ester.

Preferably, pharmaceutical compositions and dosage forms contain greater than about 25% by weight of the active ingredient (i.e., thalidomide, or a pharmaceutically acceptable prodrug, salt, solvate, hydrate, or clathrate thereof). The invention encompasses pharmaceutical compositions and dosage forms containing 30 to about 50 wt.%, preferably about 35 to about 45 wt.%, most preferably about 40 wt.% of active ingredient relative to the total amount of the composition or dosage form.

The pharmaceutical compositions and dosage forms of the present invention contain less than about 75% by weight of one or more excipients relative to the total amount of the composition or dosage form. The pharmaceutical compositions and dosage forms encompassed by the present invention contain about 50 to about 70 weight percent, preferably about 55 to about 65 weight percent, more preferably about 60 weight percent, of excipients.

Excipients include carriers, diluents, fillers, lubricants, and glidants. One embodiment of the invention includes a pharmaceutical composition comprising thalidomide, and a carrier, diluent, or filler. The amount of carrier, diluent or filler is preferably from about 50 to about 75 wt%, preferably from about 55 to about 65 wt%. Preferred pharmaceutical compositions further comprise from about 0.01 to about 4 weight percent, more preferably from about 0.1 to about 1 weight percent of a lubricant or glidant. In another embodiment, the composition further comprises a disintegrant, preferably in an amount of about 1 to about 8 weight percent, more preferably about 1 to about 3 weight percent.

Carriers, diluents, and fillers suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, tribasic calcium sulfate (tribasic calcium sulfate), carboxymethylcellulose calcium, cellulose (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, and cellulose acetate), dextrates, dextrin, dextrose (glucose), fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, matitol, maltodextrin, maltose, sorbitol, starch (e.g., pregelatinized starch), sucrose, sugar, and xylitol.

An example of a pregelatinized starch is SPRESS B-820. Suitable forms of microcrystalline cellulose include, but are not limited to, commercially available materials such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), PROSOLV SMCC 90HD (Penwest, Patterson, N.Y.), and mixtures thereof. Carriers, diluents and fillers may also be used in the premix.

Lubricants that may be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, calcium stearate, ethyl oleate, ethyl laurate, glycerol, glyceryl palmitostearate, hydrogenated vegetable oils (e.g., corn oil, cottonseed oil, olive oil, peanut oil, sesame oil, soybean oil, and sunflower oil), magnesium oxide, magnesium stearate, mannitol, poloxamers, glycols (e.g., polyethylene glycol), sodium benzoate, sodium lauryl sulfate, sodium stearate, sorbitol, stearic acid, talc, zinc stearate, and mixtures thereof.

Glidants include, for example, synthetic silica colloidal silica solidification aerosol, magnesium trisilicate, powdered cellulose, fumed silica products (e.g., CAB-O-SIL sold by Cabot co. of Boston, MA), starch, silicate silica gel (e.g., AEROSIL200, manufactured by w.r. grace co. of Baltimore, MD), talc, calcium phosphate, and mixtures thereof. If a lubricant is used, the lubricant is generally used in an amount of less than about 1% by weight relative to the pharmaceutical composition or dosage form into which it is to be incorporated.

The composition of the present invention uses a disintegrant for disintegration of the tablet when the tablet is exposed to a liquid phase environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate at a desired rate or under desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to adversely alter the release of the active ingredient should be used to form the compositions of the present invention. The amount of disintegrant used will vary from dosage form to dosage form and can be readily determined by one skilled in the art. Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, algins (e.g., alginic acid), calcium carbonate, carboxymethylcellulose, cellulose (e.g., hydroxypropyl cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose), clays, colloidal silicon dioxide, croscarmellose sodium, crospovidone, resins, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium carboxymethyl starch, starches (e.g., pregelatinized starch, potato starch, and tapioca starch), and mixtures thereof.

The pharmaceutical compositions and dosage forms may also contain wetting agents, emulsifying agents, and pH buffering agents.

The pharmaceutical compositions of the present invention are suitable for administration as discrete dosage forms such as capsules (e.g., gelatin capsules), caplets (caplets), tablets, lozenges, troches, dispersions and suppositories, each containing a predetermined amount of an active ingredient in the form of: powders, granules, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil liquid emulsions. Because of the ease of administration, tablets, caplets, and capsules represent the preferred oral dosage unit form.

Preferred tablets, caplets and capsules contain from about 50 to about 500mg of the pharmaceutical composition (i.e., active ingredient and excipients)), more preferably from about 125mg to about 500mg of the pharmaceutical composition. Particular single unit dosage forms of the invention contain 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 750 or 1000mg of the active ingredient. The capsules may be of any size. Examples of standard sizes include #000, #00, #0, #1, #2, #3, #4, # 5. See, for example, Remington's Pharmaceutical Sciences, 1658-. Preferred capsules of the invention are of size #0, #2 or # 4.

Particular embodiments of the present invention include single unit dosage forms weighing about 125mg, of which about 50mg is the active ingredient. In this embodiment, the composition is preferably encapsulated in a #4 capsule. Another embodiment weighs about 250mg, wherein about 100mg is the active ingredient. In this embodiment, the composition is preferably encapsulated in a #2 capsule. Another single unit dosage form weighs about 500mg and contains about 200mg of the active ingredient. In this embodiment, the composition is preferably encapsulated in a #0 capsule.

Table 1 illustrates examples of oral dosage forms of thalidomide of the present invention.

TABLE 1 Encapsulated thalidomide dosages

Capsule size Capsule weight (mg) thalidomide dose (mg)

#0 500 200

#2 250 100

#4 125 50

The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can promote the degradation of certain compounds. For example, it is generally accepted in the pharmaceutical arts to add (e.g., 5%) water as a means of simulating shelf life, i.e., long term storage, to characterize the formulation as its shelf life or formulation stability over time. See, for example, Jens t. carstensen, Drug Stability: principles & Practice, version 2, Marcel Deicker, NY, NY, 1995, pages 379-80. Water and heat effectively promote decomposition. Thus, the effect of water on the formulation is important because of the moisture and/or humidity often encountered during manufacture, handling, packaging, storage, transportation and use of the formulation.

Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous nature is maintained. Thus, the anhydrous composition is preferably packaged using materials known to prevent contact with water, such that the anhydrous composition can be included in a suitable kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics and the like, unit dose containers, blister packs and strip packs.

In this regard, the present invention includes a method of preparing a solid pharmaceutical formulation comprising an active ingredient by mixing the active ingredient and an excipient under anhydrous or low moisture/humidity conditions, wherein each ingredient contains substantially no water. The method may further comprise packaging the anhydrous or non-hygroscopic solid formulation under low humidity conditions. By using such conditions, the risk of contact with water is reduced and degradation of the active ingredient can be prevented or substantially reduced.

The invention further includes lactose-free pharmaceutical compositions and dosage forms. Compositions and dosage forms comprising primary or secondary amine active ingredients are preferably lactose-free, as used herein, the term "lactose-free" means that lactose is present in an amount insufficient to substantially increase the degradation rate of the primary or secondary amine active ingredient.

The lactose-free compositions of the present invention may comprise excipients well known in the art and listed in USP (XXI)/NF (XVI), which are incorporated herein. Typically, lactose-free compositions comprise pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredient, binder/filler and lubricant. Preferred lactose-free dosage forms comprise the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

4.2.Preparation process of dosage form

The dosage forms of the present invention may be prepared by pharmaceutical methods, but all methods include methods of combining the active ingredient with excipients that make up one or more of the necessary ingredients. Typically, the active ingredient is intimately mixed with liquid excipients or finely divided solid excipients, or both, and the product is then, if necessary, shaped into the desired presentation form. If desired, the tablets may be coated by standard aqueous or anhydrous techniques.

The tablets or caplets of the invention may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients and/or surfactants or dispersants as described above. Shaped tablets may be prepared by shaping in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Encapsulation of the dosage form of the present invention may be performed using methylcellulose, calcium alginate or gelatin capsules.

4.2.1.Sieving

The process for preparing the pharmaceutical composition of the present invention preferably comprises sieving of the active ingredient and excipients. Preferably, through a screen having openings of about 430 to about 750 microns. More preferably, the active ingredient is passed through a screen having openings ranging from about 600 to about 720 microns. In one embodiment, thalidomide is passed through a sieve having openings of about 710 microns. The mesh size may vary depending on the excipient used. For example, the disintegrant and binder preferably pass through pores of about 430 to about 750 microns, more preferably through pores of about 600 to about 720 microns, and most preferably through pores of about 710 microns. The lubricant preferably passes through relatively small pores, such as a mesh of about 150 to about 250 microns. In one embodiment, the lubricant passes through a mesh opening of about 210 microns.

4.2.2.Premixing

After the ingredients are sieved, the excipients and the active ingredient are preferably mixed in a diffusion mixer (dispersion mixer). In one embodiment, the mixing time is from about 1 to about 50 minutes, preferably from about 5 to about 45 minutes, more preferably the mixing time is from about 10 to about 40 minutes, most preferably from about 10 to about 25 minutes. In another embodiment, the stirring time is about 15 minutes.

When more than one excipient is used, the excipients may be mixed in a tank mixer (tumbler blender) for about 1 to about 20 minutes, preferably about 5 to about 10 minutes, before the excipients are mixed with the active ingredient.

4.2.3.Roller compaction

In one embodiment, the pre-mix may be passed through a roller mill having a hammer mill at its discharge.

4.2.4.Final mixing

When a lubricant such as magnesium stearate is used, the lubricant is mixed with the premix at the end of the process to provide the pharmaceutical composition. This additional mixing time is preferably from about 1 to about 10 minutes, more preferably from about 3 to about 5 minutes.

4.2.5.Capsule

The formulation mixture is then loaded into capsule shells of the desired size using, for example, a capsule filling machine or a rotary tablet press.

4.3. Reagent kit

Pharmaceutical packages or kits comprising a pharmaceutical composition or dosage form disclosed herein are also encompassed by the present invention. An example of a kit is one that includes instructions described by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which agency reflects approval by the agency for the manufacture, use or sale of human beings.

4.4.Methods of treatment and prevention

The invention also relates to methods of treating and preventing various diseases and conditions in a patient (e.g., mammals including humans). Examples of such diseases and disorders include, but are not limited to, leprosy, chronic graft-versus-host disease, rheumatoid arthritis, sarcoidosis, inflammatory disease disorders (e.g., dermatitis), inflammatory bowel disease, and cancer. Examples of cancers that may be treated using the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, primary and metastatic cancers of the head, neck, eyes, mouth, throat, subcutaneous tissue, lymph nodes, esophagus, chest, bone, intestine, lung, colon, rectum, stomach, heart, prostate, breast, ovary, adrenal gland, kidney, liver, pancreas, and brain. Specific examples of treatable cancers include, but are not limited to, aids-related leukemia and adult T-cell leukemia; anal cancer; astrocytoma; biliary tract tumors; bladder cancer, including bladder cancer; brain cancer, including glioblastoma and medulloblastoma; breast cancer, including mastadenoma; uterine cancer; choriocarcinoma; colon cancer, including colorectal carcinoma; endometrial cancer; esophageal cancer; ewing's sarcoma; gastric cancer; gestational nourishing layered tumor; glioma; hairy cell leukemia; head and neck tumors; hematological tumors, including acute and chronic lymphocytic and myelogenous leukemias; hepatoma; kaposi's sarcoma; kidney cancer; multiple myeloma; epitheliomas, including cutaneous carcinoma in situ (Bowen's disease) and paget's disease; liver cancer; lung cancer, including small cell carcinoma; lymphomas, including hodgkin's disease, lymphocytic lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, diffuse large cell lymphoma, follicular mixed cell lymphoma, and lymphoblastic lymphoma; lymphocytic leukemia; neuroblastoma; oral cancer, including squamous cell carcinoma; ovarian cancers, including those generated from epithelial, mesenchymal, germ and mesenchymal cells; pancreatic cancer; prostate cancer; rectal cancer; sarcomas, including soft tissue tumors, leiomyosarcoma, rhabdomyosarcoma, liposarcoma (liposcarcoma), fibrosarcoma, and osteosarcoma; skin cancers including melanoma, kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma; testicular cancer, including testicular and germ cell tumors (e.g., seminoma, non-seminoma [ teratoma, choriocarcinoma ]); stromal tumors and germ cell tumors; thyroid cancer, including thyroid adenoma and medullary tumor; and kidney cancers including adenocarcinoma and Wilm's tumor. The term "colorectal cancer" refers to diseases of the colon, sigmoid colon and/or rectum and skin tissues, organs, blood and blood vessels adjacent to the colon, sigmoid colon and/or rectum.

Other diseases and disorders that may be treated using the pharmaceutical compositions of the present invention are disclosed in U.S. Pat. Nos. 5,712,291 and 6,235,756 to D' Amato, both of which are incorporated herein by reference.

The invention also includes a method of reducing or preventing side effects associated with chemotherapy and radiation therapy comprising administering to a patient in need of such treatment or prevention a pharmaceutical composition or dosage form of the invention in an amount sufficient to reduce the side effects associated with chemotherapy and radiation therapy. This embodiment includes the use of a pharmaceutical composition or dosage form to protect against or treat side effects associated with the use of chemotherapy or radiation therapy, including increasing the patient's tolerance to chemotherapy or radiation therapy.

Examples of side effects associated with chemotherapy and radiotherapy include, but are not limited to: gastrointestinal toxicity such as, but not limited to, diarrhea and flatulence from morning to evening; nausea; vomiting; anorexia; leukopenia; anemia; neutropenia; frailty; abdominal cramps; fever is caused; pain; weight loss; dehydrating; alopecia; dyspnea; insomnia; dizziness, mucositis, xerostomia, and renal failure.

The amount of active ingredient actually administered to a patient will vary depending on a number of factors such as, but not limited to, the disease or condition being treated or prevented, the particular active ingredient, and the method of administration. For example, the dosage and/or frequency of administration can also vary depending on the age, weight, response, and history of the patient. Appropriate dosage regimens can be readily selected by those skilled in the art, with appropriate consideration of literature reports and Physician's desk reference(55 th edition, 2001) of the recommended dose.

In one embodiment of the invention, the daily oral dose of the active ingredient is from about 50 to about 2000mg, preferably from about 50 to about 1000mg, more preferably from about 50 to 800 mg. In a preferred embodiment, a dosage of about 200 to about 800mg of the active ingredient is recommended.

Examples

Embodiments of the present invention will be more fully understood by those skilled in the art with reference to the following examples. However, these examples are intended to illustrate the pharmaceutical compositions and dosage forms of the present invention and the present invention is not limited by the following examples. All parts are by weight unless otherwise indicated.

5.1.Example 1: capsules of 200MG thalidomide dosage

Table 2 illustrates the batch and single dose formulations of 200mg, i.e., about 40% by weight thalidomide single dose unit #0 capsules

TABLE 2200 mg thalidomide Capsule formulation

Material	By weight%	Quantity (mg/tablet)	Quantity (kg/batch)
				Thalidomide	40.0％	200mg	16.80kg
Pregelatinized corn starch, NF	59.5％	297.5mg	24.99kg
				Magnesium stearate	0.5％	2.5mg	0.21kg
Total of	100.0％	500mg	42.00kg

The pregelatinized starch (SPRESS B-820) and thalidomide components were passed through a 710 micron sieve and then mixed in a diffusion blender with baffle insert for 15 minutes. Magnesium stearate was passed through a 210 micron sieve and then added to a diffusion blender, and the mixture was encapsulated in #0 capsules weighing 500mg per capsule using a Dosator type capsule filling machine (8400 capsules per batch).

5.2.Example 2: tablet of 100MG thalidomide dosage

Table 3 illustrates the batch and single dose unit formulations of 100mg, i.e. 40 wt% thalidomide single dose unit tablets.

TABLE 3100 mg thalidomide tablet formulation

Material	By weight%	Quantity (mg/tablet)	Quantity (kgg/batch)
				Thalidomide	40％	100.00	20.00
Microcrystalline cellulose, NF	53.5％	133.75	26.75
				Pluronic F-68 surfactant	4.0％	10.00	2.00
Type A croscarmellose sodium, NF	2.0％	5.00	1.00
				Magnesium stearate, NF	0.5％	1.25	0.25
Total of	100.0％	250.00mg	50.00kg

The microcrystalline cellulose, croscarmellose sodium, and thalidomide components were passed through a 30 mesh screen (about 430 μ to about 655 μ). Pluronic F-68(produced by JRH Biosciences, Inc. of Lenexa, KS) through a 20 mesh screen (about 457. mu. to about 1041. mu.). Pluronic F-68 surfactant and 0.5kg of croscarmellose sodium were added to a double barrel mixer at 16qt. and mixed for about 5 minutes, the mixture was transferred to a 3 cubic foot double shell tumble mixer to which microcrystalline cellulose was added and mixed for about 5 minutes. Then addAdd thalidomide and mix for an additional 25 minutes. The premix is passed through a roller mill with a hammer mill at the discharge of the roller mill and returned to the tank mixer. The remaining croscarmellose sodium and magnesium stearate are then added to the tank mixer and mixed for about 3 minutes. The final blend was compressed in a rotary tablet press to a weight of 250mg per tablet (200,000 tablets per batch).

5.3.Example 3: prior art dosage units of thalidomide

Table 4 illustrates the prior art batch and single dose unit formulations of 50mg, i.e. 12.5 wt% thalidomide single dose unit #0 capsules.

TABLE 450 mg thalidomide #0 Single dose Unit formulation

Material	By weight%	Quantity (mg/tablet)	Quantity (kg/batch)
				Thalidomide	12.5％	50.0	7.50
Microcrystalline cellulose	15.0％	60.0	9.00
				Kollidon 90F USP1	3.0％	12.0	1.80
Stearic acid NF	1.0％	4.0	0.60
				Colloidal silica	0.2％	0.8	0.12
Crospovidone NF	4.0％	16.0	2.40
				Lactose anhydrous NF	64.3％	257.3	38.58
Total of	100.0％	400.0mg	60.00kg

¹Also produced by BASF as Povidone 90F USP

Microcrystalline cellulose, KOLLIDON 90F, stearic acid, colloidal silicon dioxide, crospovidone, and anhydrous lactose were weighed separately and passed through a 710 μ sieve. The material was transferred to a roll Fielder mixer. Then, the milled thalidomide was weighed and added to the raw material through a sieve, followed by the addition of anhydrous lactose. The mixture is stirred for about 2.5 minutes to about 6 minutes until the mixture is well mixed. The mixture was compressed by passing it through a roller compactor (Mexanderwerk compact WP 50N175), and then encapsulated using a Zanasi Az20 encapsulation machine (150,000 capsules per batch). The mixture was filled into a #0 hard capsule to contain the desired fill weight of powder and 50mg of thalidomide.

Although the present invention has been described with reference to specific embodiments, various changes or modifications may be made by one skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims. Such variations are intended to fall within the scope of the present claims.

Claims (3)

1. A pharmaceutical composition in the form of a #4 capsule weighing 125mg and containing 74.375mg pregelatinized corn starch, 50mg thalidomide and 0.625mg magnesium stearate.
2. Pharmaceutical composition in the form of a #2 capsule weighing 250mg and containing 148.75mg pregelatinized corn starch, 100mg thalidomide and 1.25mg magnesium stearate.
3. A pharmaceutical composition in the form of a #0 capsule weighing 500mg and containing 297.5mg pregelatinized corn starch, 200mg thalidomide and 2.5mg magnesium stearate.