Formulation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, and represents an oral dosage form in the form of capsule, containing: 1) pomalidomide in the amount of 0.1 to 3 wt % of total weight; 2) a binding agent or an excipient in the amount of 90 to 99 wt % of total weight wherein the binding agent or the excipient represent starch, mannitol or their mixture.

EFFECT: invention provides stability of the declared dosage form.

22 cl, 7 ex, 6 tbl

 

1. The technical field to which the invention relates

Disclosed compositions and dosage forms pomalidomide, i.e. the 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione or CC-4047. Also disclosed methods of applying the compositions and dosage forms.

2. Prior art

Pharmaceutical substances for medicinal drugs are usually administered in the form of component compositions in combination with one or more other substances that perform different specialized functions. Dosage forms of various types can be prepared at selective use of pharmaceutical excipients. Pharmaceutical fillers have different functions and contribute to pharmaceutical compositions in many different ways, for example, leading to solubilization, breeding, thickening, stabilization, preservation, staining, giving a taste and smell, etc. Properties, which usually take into account in the formulation of the active substance include bioavailability, ease of production, ease of implementation and stability of dosage forms. Taking into account various properties of the active substance subject formulations are, as a rule, for a pharmaceutical forms choose pharmaceutical excipients that are uniquely fitted to the active substance for the achievement of improved physical and pharmacy properties.

Pomalidomide, also known as CC-4047, chemically, is a 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Pomalidomide is an immunomodulator that inhibits, for example, the production of monocyte TNFα, IL-1β, IL-12, IL-6, MIP-1, MCP-1, GM-CSF, G-CSF and COX-2 induced by LPS. Also know that the connection will costimulatory activation of T cells. Pomalidomide and the method of synthesis of the compounds described, for example, in U.S. patent No. 5635517, which fully included in this document for details.

Because of the diversity of pharmacological properties pomalidomide is suitable for treatment, prevention and/or control of various diseases or disorders. Thus, there is a need for dosage forms pomalidomide with preferred physical and pharmaceutical properties.

3. The invention

Disclosed pharmaceutical dosage forms pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate. Also disclosed methods of treatment, management or prevention of diseases or conditions, such as, without limitation, cancer, pain, macular degeneration, skin disease, lung disease, illness caused by exposure to asbestos, a parasitic disease, immunodeficiency, disorder of the Central nervous system, damage to the Central nervous system, atherosclerosis, sleep disorders, hemoglobinopathies, anemia, autoimmune disease, viral disease, hereditary disease, allergic disease, bacterial disease, neovascularization of the eye, choroidal neovascularization, neovascularization of the retina and robes using pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in the dosage forms described in this document.

3.1. Definitions

In the sense in which this document is used, and unless otherwise specified, the term composition which essentially contains no connection" means that the composition contains less than about 20 wt.%, more preferably less than about 10 wt.%, even more preferably less than about 5 wt.% and most preferably less than about 3 wt.% connection.

In the sense in which this document is used, and unless otherwise specified, the term "stereoisomer clean", he means a composition that contains one stereoisomer of the compound and essentially contains no other stereoisomers of the compound. For example, stereoisomers pure composition of compounds containing one chiral center, essentially will not contain the opposite of enantio the EP connection. Stereoisomers pure composition of a compound containing two chiral center, essentially will not contain other diastereoisomer connection. Typical stereoisomers pure compound contains more than 80 wt.% one stereoisomer of the compound and less than about 20 wt.% other stereoisomers of the compound, more preferably more than about 90 wt.% one stereoisomer of the compound and less than about 10 wt.% other stereoisomers of the compound, even more preferably more than about 95 wt.% one stereoisomer of the compound and less than about 5 wt.% other stereoisomers of the compound, and most preferably more than about 97 wt.% one stereoisomer of the compound and less than about 3 wt.% other stereoisomers of the compound.

In the sense in which this document is used, and unless otherwise specified, the term "enantiomerically pure", it means stereoisomers pure composition of compounds containing one chiral center.

In the sense in which this document is used, and unless otherwise specified, the term "pharmaceutically acceptable salt(s)", it includes, but is not limited to, salts of acidic and basic groups of thalidomide. Basic group capable of forming a wide variety of salts with various inorganic and organic acids. Acid, which can the be used to obtain pharmaceutically acceptable additive acid salts of such basic compounds, are acid forming non-toxic additive salt of the acid, i.e. salts containing pharmacologically acceptable anions. Suitable organic acids include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, almond, cinnamony, oleic, tanning, aspartic, stearic, palmitic, glycolic acid, glutamic, gluconic, glucuronic, sugar, isonicotinoyl, methansulfonate, econsultancy, p-toluensulfonate, benzosulfimide or Paveway (i.e. 1,1'-methylene-bis-(2-hydroxy-3-aftout) acid. Suitable inorganic acids include, but are not limited to, hydrochloric, Hydrobromic, idiscovered, sulfuric, phosphoric or nitric acid. Compounds that contain an amino group, capable of forming pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Chemical groups that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts are salts of alkali metals or alkaline earth metals, and, in particular, calcium, magnesium, sodium, lithium, zinc, potassium or iron.

p> In the sense in which this document is used, and unless otherwise specified, the term "MES", it means the connection described in this document, or its salt, which further includes a stoichiometric or non-stoichiometric amount of solvent bound non-covalent intermolecular bonds. In the case when the solvent is water, the MES is a hydrate.

In the sense in which this document is used, and unless otherwise specified, the term "prodrug", he means derived compound, which may be subjected to hydrolysis, oxidation or interact otherwise in biological conditions (in vitro or in vivo) with the formation of the original connection. Examples of prodrugs include, but are not limited to, derivatives of thalidomide containing biohydrology groups, such as biokerosene amides, biohydrology esters, biohydrology carbamates, biohydrology carbonates, biohydrology ureides and biokerosene phosphates. Other examples of prodrugs include derivatives of thalidomide containing group,- NO, -NO2, -ONO, or-ONO2.

In the sense in which this document uses, and unless otherwise specified, the terms "biohydrology carbamate", "biohydrology carbonate", "biohydrology of wreid" and "biohydrology the initial phosphate", they mean, respectively, carbamate, carbonate, wreid or phosphate compounds that are: 1) do not adversely affect the biological activity of compounds, but can make the connection improved properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of "biohydrology carbamates include, but not be limited to, lower alkylamines followed, substituted Ethylenediamine, amino acids, hydroxyethylamine, heterocyclic or heteroaromatic amines and polyetheramines.

In the sense in which this document is used, and unless otherwise specified, the term "biohydrology ester",it means an ester compound, which is: 1) do not adversely affect the biological activity of compounds, but can make the connection improved properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of "biohydrology esters" include, but are not limited to, lower alkalemia esters, alkoxylation, alchilcicloalchilsulfai esters and with whom you kalinovye esters.

In the sense in which this document is used, and unless otherwise specified, the term "biohydrology amide",it means amide compounds, which: 1) do not adversely affect the biological activity of compounds, but can make the connection improved properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of "biohydrology amides" include, but are not limited to, lower alkylamide, amides of α-amino acids, alkoxysilane and alkylaminocarbonyl.

In the sense in which this document uses, and unless otherwise specified, the terms "treat", "treatment" and "treatment", they assume the action that occurs when the patient is suffering from a specific disease or disorder, which leads to decrease the severity of the disease or disorder, or inhibits or slows the progression of the disease or disorder.

In the sense in which this document uses, and unless otherwise specified, the terms "prevent", "preventing" and "prevention", they refer to early warning, recurrence or progression of the disease or disorder, or one, Il is more than its symptoms. The terms "prevent", "preventing" and "prevention" suggest an action that occurs before a patient begins to suffer from a particular disease or disorder, which leads to the suppression or reduction of the severity of the disease or disorder.

In the sense in which this document uses, and unless otherwise specified, the terms "controlling," "process control" and "control", they include the prevention of the recurrence of a certain disease or disorder in a patient who is already suffering from a disease or disorder, and/or lengthening the period of time during which the patient is afflicted with a disease or disorder remains in remission. The term includes the modulation threshold, progression, and/or duration of the disease or disorder, or the nature of the reactions, how the patient responds to the cause of the disease or disorder.

In the sense in which this document is used, and unless otherwise specified, the term "about"when used in relation to the doses, the quantity or mass percent of the ingredients in the composition or dosage form, dose, number or mass percentage, known to specialists in this field, to provide pharmacological effect, equivalentes is received from a specific dose, the quantity or mass percent. In particular, the term "about" includes the dose, quantity, or mass percentage within 30%, 25%, 20%, 15%, 10% or 5% of a specific dose, amount, or weight percent.

In the sense in which this document is used, and unless otherwise specified, the term "stable relative to the composition or dosage form, it means that the active ingredient in the composition or the dosage form remains in solubilization condition within a certain period of time and does not significantly degrade or aggregates, or becomes otherwise modified (for example, according to HPLC). In some embodiments, the implementation of about 70% or higher, about 80% or greater, or about 90% or higher connection remains solubilizing after a certain period of time.

4. Detailed description of the invention

Disclosed pharmaceutical dosage forms pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate. In some embodiments, the implementation of the dosage forms suitable for oral administration to a patient. In other embodiments, implementation of the dosage forms disclosed herein exhibit improved physical and/or pharmacological properties. Such properties VK is ucaut, not limited to, ease of analysis, the homogeneity of the composition, the flowability for production, dissolution and bioavailability, and stability. In some embodiments, the implementation of the dosage forms disclosed in this document, have a half-life of at least about 12 months, at least about 24 months, or at least about 36 months when stored without refrigeration.

Also disclosed kits containing pharmaceutical compositions and dosage forms described herein. Also disclosed methods of treatment, control and/or prevention of a disease or condition, which includes the introduction of a patient in need this, pharmaceutical compositions or dosage forms described in this document.

4.1. Compositions and dosage forms

In one embodiment, herein is disclosed a separate single dosage form suitable for oral administration to man, containing the amount of active ingredient equal to or greater than about 1; 5; 10; 15; 20; 25; 30; 50; 75; 100; 150 or 200 mg; and pharmaceutically acceptable filler, in which the active ingredient is pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate. In some embodiments, domestic the amount of the active ingredient is in the range from about 0.1 to about 100 mg, from about 0.5 to about 50 mg, from about 0.5 to about 25 mg, from about 1 to about 10 mg, from about 0.5 to about 5 mg or about 1 to about 5 mg. In one embodiment, the amount of active ingredient is about 0.5 mg In another embodiment, the amount of active ingredient is about 1 mg. In yet another embodiment, the amount of active ingredient is about 2 mg In another embodiment, the amount of active ingredient is about 5 mg.

Pharmaceutical compositions and preparative forms described herein, may be in separate dosage forms, such as capsules (e.g., gelcaps), tablets, capsules, pills, tablets, sucking tablets, dispersions and suppositories, where each form contains a predetermined amount of the active ingredient in the form of powder or granules, a solution or suspension in an aqueous or nonaqueous liquid, emulsion, oil-in-water or emulsion water-in-oil. Due to the simplicity of the introduction of tablets, pills, capsules and capsules are the preferred single dosage forms.

Typically, tablets, pills, capsules and the capsules contain from about 50 mg to about 500 mg of the pharmaceutical composition (i.e. the active ingredient of the filler(s)). Capsules can be of any size. Examples of standard sizes include№000, №00, №0, №1, №2, №3, №4 and # 5. See, for example, Remington's Pharmaceutical Sciences, page 1658-1659 (Alfonso Gennaro ed., Mack Publishing Company, Easton Pennsylvania, 18thed., 1990), this source is included in this document for details. In some embodiments, the implementation of the capsules disclosed herein have a size No. 1 or more, 2 or more, or No. 4 or more.

Also herein disclosed anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, since water can facilitate the degradation of some compounds. For example, the addition of water (for example, 5%) is widely used in pharmacy as a way to model half-life, i.e. a long storage period, to determine characteristics such as half-life or stability of the compositions over time. See, for example, Jens T. Cartensen, Drug Stability: Principles&Practice, 2d Ed., Marcel Dekker, NY, NY, 1995, pp. 379-380. In fact, water and heat accelerate decomposition. Thus, the effect of water on the composition can have a very great importance, because the moisture and/or humidity are common factors during production, handling, packaging, storage, transportation and application of compositions.

Anhydrous pharmaceutical compositions should be prepared and stored in such a way, stabilograms their anhydrous state. Therefore, in some embodiments, the implementation of the anhydrous compositions are packaged using materials known that they prevent the action of water, so that it can be included in a suitable formulated sets. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic or the like, a container for discrete dosage forms, blister and strip packaging.

In this respect, also in this document discloses a method of obtaining a solid pharmaceutical composition containing the active ingredient by mixing the active ingredient and filler in anhydrous conditions and/or conditions with low moisture content/humidity, in which the ingredients are essentially does not contain water. The method may further include packaging anhydrous or non-hygroscopic solid composition in conditions of low humidity. When using such conditions the risk of contact with water is reduced, and the decomposition of the active ingredient can be prevented and significantly reduce.

Also in this document are disclosed pharmaceutical compositions and dosage forms that do not contain lactose. Compositions and dosage forms containing the active ingredient, which represents a primary or secondary amine, preferably the e contain lactose. In the sense in which this document uses the term "does not contain lactose", it means that the amount of lactose present, if it is in the composition is insufficient to significantly increase the speed of decomposition of the active ingredient, which represents a primary or secondary amine. Does not contain lactose compositions disclosed herein can contain fillers, well known in this area and listed in the US Pharmacopoeia (USP (XXI)/NF (XVI)), this source is included in this document for details.

In one embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is from about 0.1 to about 10 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is from about 0.1 to about 5 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is from about 0.1 to about 3 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prolec RSTO, salt, MES, hydrate, or clathrate is from about 0.5 to about 3 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is from about 0.5 to about 2 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is about 1 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is about 0.8 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is about 2 wt.% to the total weight of the composition. In yet another embodiment, pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate is about 1.7 wt.% to the total weight of the composition.

In one embodiment, the active ingredient and a carrier, diluent, binder, or filler are mixed, as described in this document. Another option is e implementation of the media, the diluent, binder, or filler include mannitol and/or starch. In yet another embodiment, mannitol is a spray dried mannitol. In yet another embodiment, the starch is a pre-gelatinising starch.

In one embodiment, carrier, diluent, binder, or filler comprise from about 70 to about 99 wt.% to the total weight of the composition. In yet another embodiment, the carrier, diluent, binder, or filler comprise from about 80 to about 99 wt.% to the total weight of the composition. In yet another embodiment, the carrier, diluent, binder, or filler comprise from about 85 to about 99 wt.% to the total weight of the composition. In yet another embodiment, the carrier, diluent, binder, or filler comprise from about 90 to about 99 wt.% to the total weight of the composition. In yet another embodiment, the carrier, diluent, binder, or filler comprise from about 95 to about 99 wt.% to the total weight of the composition. In yet another embodiment, the carrier, diluent, binder or aggregate amount to about 98 wt.% to the total weight of the composition. In yet another embodiment, the carrier, diluent, the connection is completed with the substance or the aggregate amount to about 99 wt.% to the total weight of the composition.

In one embodiment, dosage forms described herein contain both mannitol and starch. In one embodiment, mannitol and starch comprise from about 70 to about 99 wt.% to the total weight of the composition. In yet another embodiment, mannitol and starch comprise from about 80 to about 99 wt.% to the total weight of the composition. In yet another embodiment, mannitol and starch comprise from about 85 to about 99 wt.% to the total weight of the composition. In yet another embodiment, mannitol and starch comprise from about 90 to about 99 wt.% to the total weight of the composition. In yet another embodiment, mannitol and starch comprise from about 95 to about 99 wt.% to the total weight of the composition. In yet another embodiment, mannitol and starch make up about 98 wt.% to the total weight of the composition. In yet another embodiment, mannitol and starch make up about 99 wt.% to the total weight of the composition.

In one embodiment, the ratio of mannitol:starch in the dosage form is in the range from about 1:1 to about 1:1,5. In one embodiment, the ratio of mannitol:starch in the dosage form is about 1:1,3.

In another embodiment, dosage form contains a lubricating substance. In one embodiment, cartenna form contains approximately 0.2; 0,3; 0,5; 0,6 or 0,8 mg lubricants. In another embodiment, dosage form contains about 0,16; 0,32; 0,64 or 0.75 mg lubricants. In yet another embodiment, the lubricating substance is sodium fumarate (PRUV).

In one embodiment, a lubricating substance, such as PRUV is from about 0.01 to about 5 wt.% to the total weight of the composition. In yet another embodiment, a lubricating substance, such as PRUV is from about 0.01 to about 1 wt.% to the total weight of the composition. In yet another embodiment, a lubricating substance, such as PRUV is from about 0.1 to about 1 wt.% to the total weight of the composition. In yet another embodiment, a lubricating substance, such as PRUV is from about 0.1 to about 0.5 wt.% to the total weight of the composition. In yet another embodiment, a lubricating substance, such as PRUV is from about 0.2 to about 0.3 wt.% to the total weight of the composition. In yet another embodiment, a lubricating substance, such as PRUV, is approximately 0.25 wt.% to the total weight of the composition.

Considering the fact that usually pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate get with a purity of less than 100%, in some embodiments, the implementation of the composition and Lakers the governmental forms, described in this document, can be defined as a composition, formulation or dosage form containing pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount which provides the content of a certain quantity of 100% pure pomalidomide.

For example, in one embodiment, disclosed is a separate single dosage form containing, respectively: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide approximately 0.5; 1; 2; 3; 4 or 5 mg, and 2) about 60; 120; 250; 180; 240 and 300 mg of carrier, diluent, binder or filler. In one embodiment, the number of carrier, diluent, binder, or filler, respectively 62; 124; 248; 177; 236 or 295 mg.

In one embodiment, disclosed pharmaceutical form, containing respectively: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 0.5 mg and 2) a pharmaceutically acceptable excipient. In one embodiment, the total weight of the dosage form with what is about to 62.5 mg In one embodiment, dosage form suitable for administration in a capsule of size No. 4 or larger capsule. In one embodiment, the filler includes a carrier, diluent, binder and filler. In one embodiment, the fillers include carrier, diluent, binder, or filler, and grease.

In one embodiment, where the total weight of the dosage form is about 62.5 mg, carrier, diluent, binder, or filler include mannitol and/or starch. In one embodiment, the filler includes both mannitol and starch. In one embodiment, when the dosage form contains both mannitol and starch, the dosage form contains about 35 mg of starch, and the rest of the mass is filled with starch. In one embodiment, mannitol is spray dried mannitol. In yet another embodiment, the starch is pre-gelatinising starch.

In one embodiment, where the total weight of the dosage form is about 62.5 mg and where there is grease, the lubricating substance is sodium fumarate. In one embodiment, the sodium fumarate is the number of the ome of 0.2 mg. In one embodiment, the sodium fumarate is about 0,16 mg

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 0.5 mg; 2) approximately 35 mg pre gelatinising starch; 3) approximately 0.16 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 62.5 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 4 or larger capsule.

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 1 mg, and 2) a pharmaceutically acceptable excipient. In one embodiment, the total weight of the dosage form is about 125 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 4 or larger capsule. In one embodiment, the filler includes a carrier, a diluent, with asuume substance and a filler. In one embodiment, the fillers include carrier, diluent, binder, or filler, and grease.

In one embodiment, where the total weight of the dosage form is about 125 mg, carrier, diluent, binder, or filler include mannitol and/or starch. In one embodiment, the filler includes both mannitol and starch. In one embodiment, when the dosage form contains both mannitol and starch, the dosage form contains about 70 mg of starch, and the rest of the mass is filled with starch. In one embodiment, mannitol is spray dried mannitol. In yet another embodiment, the starch is pre-gelatinising starch.

In one embodiment, where the total weight of the dosage form is about 125 mg and where there is grease, the lubricating substance is sodium fumarate. In one embodiment, the fumarate sodium is in the amount of about 0.3 mg. In one embodiment, the sodium fumarate is about 0,32 mg

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically pickup is acceptable stereoisomer, the prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 1 mg; 2) about 70 mg pre gelatinising starch; 3) about 0,32 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 125 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 4 or larger capsule.

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 2 mg, and 2) a pharmaceutically acceptable excipient. In one embodiment, the total weight of the dosage form is about 250 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 2 or larger capsule. In one embodiment, the filler includes a carrier, diluent, binder and filler. In one embodiment, the fillers include carrier, diluent, binder, or filler, and grease.

In one embodiment, where the total mass of the dosage forms what is about 250 mg, the carrier, diluent, binder, or filler include mannitol and/or starch. In one embodiment, the filler includes both mannitol and starch. In one embodiment, when the dosage form contains both mannitol and starch, the dosage form contains about 140 mg of starch, and the rest of the mass is filled with starch. In one embodiment, mannitol is spray dried mannitol. In yet another embodiment, the starch is pre-gelatinising starch.

In one embodiment, where the total weight of the dosage form is about 250 mg and where there is grease, the lubricating substance is sodium fumarate. In one embodiment, the fumarate sodium is in the amount of approximately 0.6 mg In one embodiment, the sodium fumarate is about 0,64 mg

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 2 mg; 2) approximately 140 mg pre gelatinising starch; 3) approximately 0.64 mg stearyl the Marat of sodium and 4) spray dried mannitol in amounts which brings the total weight of the dosage form to 250 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 2 or larger capsule.

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 3 mg, and 2) a pharmaceutically acceptable excipient. In one embodiment, the total weight of the dosage form is about 180 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 2 or larger capsule. In one embodiment, the filler includes a carrier, diluent, binder and filler. In one embodiment, the fillers include carrier, diluent, binder, or filler, and grease.

In one embodiment, where the total weight of the dosage form is about 180 mg, carrier, diluent, binder, or filler include mannitol and/or starch. In one embodiment, the filler includes both mannitol and starch. In one embodiment, when the dosage form is present on the simultaneous mannitol and starch, the dosage form contains about 100 mg of starch, and the rest of the mass is filled with starch. In one embodiment, mannitol is spray dried mannitol. In yet another embodiment, the starch is pre-gelatinising starch.

In one embodiment, where the total weight of the dosage form is about 180 mg and where there is grease, the lubricating substance is sodium fumarate. In one embodiment, the fumarate sodium is in the amount of about 0.5 mg. In one embodiment, the sodium fumarate is about 0,45 mg

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 3 mg; 2) about to 100.8 mg pre gelatinising starch; 3) approximately 0.45 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 180 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 2 or larger capsule.

In one embodiment, skryvaetsja dosage form, containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 4 mg, and 2) a pharmaceutically acceptable excipient. In one embodiment, the total weight of the dosage form is about 240 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 2 or larger capsule. In one embodiment, the filler includes a carrier, diluent, binder and filler. In one embodiment, the fillers include carrier, diluent, binder, or filler, and grease.

In one embodiment, where the total weight of the dosage form is about 240 mg, carrier, diluent, binder, or filler include mannitol and/or starch. In one embodiment, the filler includes both mannitol and starch. In one embodiment, when the dosage form contains both mannitol and starch, the dosage form contains about 135 mg of starch, and the rest of the mass is filled with starch. In one embodiment, mannitol is spray dried mannitol. In yet another embodiment, krahm the l represents the pre-gelatinising starch.

In one embodiment, where the total weight of the dosage form is about 240 mg and where there is grease, the lubricating substance is sodium fumarate. In one embodiment, the fumarate sodium is in the amount of approximately 0.6 mg

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 4 mg; 2) approximately RUR 134.4 mg pre gelatinising starch; 3) approximately 0.6 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 240 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 2 or larger capsule.

In one embodiment, disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 5 mg, and 2) a pharmaceutically acceptable excipient. In one embodiment, the total weight of the dosage form is about 300 mg. what one embodiment, dosage form suitable for administration in a capsule of size No. 1 or larger capsule. In one embodiment, the filler includes a carrier, diluent, binder and filler. In one embodiment, the fillers include carrier, diluent, binder, or filler, and grease.

In one embodiment, where the total weight of the dosage form is about 300 mg, carrier, diluent, binder, or filler include mannitol and/or starch. In one embodiment, the filler includes both mannitol and starch. In one embodiment, when the dosage form contains both mannitol and starch, the dosage form contains about 168 mg of starch, and the rest of the mass is filled with starch. In one embodiment, mannitol is spray dried mannitol. In yet another embodiment, the starch is pre-gelatinising starch.

In one embodiment, where the total weight of the dosage form is about 300 mg and where there is grease, the lubricating substance is sodium fumarate. In one embodiment, the fumarate sodium is in the amount of about 0.8 mg. In one embodiment, the fumarate sodium is in the amount of about 0.75 mg

In one var is ante implementation of the disclosed dosage form, containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 5 mg; 2) approximately 168 mg pre gelatinising starch; 3) to about 0.75 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 300 mg. In one embodiment, dosage form suitable for administration in a capsule of size No. 1 or larger capsule.

In yet another embodiment, disclosed dosage form containing pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 0.5 mg, which is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In some embodiments, the implementation of the dosage form contains mannitol and/or starch. In one embodiment, when the dosage form contains both mannitol and starch, the starch is in an amount of about 35 mg and mannitol is the amount that brings the total weight of the dosage form to 62.5 mg In some embodiments, realized what I dosage form further comprises a fumarate sodium in an amount of about 0.2 mg, or about 0,16 mg In some embodiments, implementation of the disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 0.5 mg; 2) approximately 35 mg pre gelatinising starch; 3) approximately 0.16 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 62.5 mg; where the dosage form is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In one embodiment, dosage form suitable for administration in a capsule of size No. 4 or larger capsule.

In yet another embodiment, disclosed dosage form containing pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 1 mg, which is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In some embodiments, the implementation of the dosage form contains mannitol and/or starch. In one embodiment, when the dosage form is rootstown both mannitol and starch, the starch is in an amount of about 70 mg and mannitol is the amount that brings the total weight of the dosage form to 125 mg. In some embodiments, the implementation of the dosage form further comprises a fumarate sodium in an amount of about 0.3 mg, or about 0,32 mg In some embodiments, implementation of the disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 1 mg; 2) about 70 mg pre gelatinising starch; 3) about 0,32 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 125 mg; where the dosage form is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In one embodiment, dosage form suitable for administration in a capsule of size No. 4 or larger capsule.

In yet another embodiment, disclosed dosage form containing pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide note the RNO 2 mg, which is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In some embodiments, the implementation of the dosage form contains mannitol and/or starch. In one embodiment, when the dosage form contains both mannitol and starch, the starch is in an amount of about 140 mg and mannitol is the amount that brings the total weight of the dosage form to 250 mg. In some embodiments, the implementation of the dosage form further comprises a fumarate sodium in an amount of about 0.6 mg or about 0,64 mg In some embodiments, implementation of the disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 2 mg; 2) approximately 140 mg pre gelatinising starch; 3) approximately 0.64 mg of sodium fumarate and 4) spray dried mannitol in an amount which brings the total weight of the dosage form to 250 mg; where the dosage form is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In one embodiment, a pharmaceutical form suitable for the conduct in the capsule of size No. 2 or larger capsule.

In yet another embodiment, disclosed dosage form containing pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 5 mg, which is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In some embodiments, the implementation of the dosage form contains mannitol and/or starch. In one embodiment, when the dosage form contains both mannitol and starch, the starch is in an amount of about 168 mg, and mannitol is the amount that brings the total weight of the dosage form to 300 mg. In some embodiments, the implementation of the dosage form further comprises a fumarate sodium in an amount of about 0.8 mg, or about 0.75 mg In some embodiments, implementation of the disclosed dosage form containing: 1) pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, in an amount to provide content pomalidomide about 5 mg; 2) about 168 mg pre gelatinising starch; 3) to about 0.75 mg of sodium fumarate and 4) spray dried mannitol in quantity is as, which brings the total weight of the dosage form, 300 mg; where the dosage form is stable for at least about 12, about 24, or about 36 months when stored without refrigeration. In one embodiment, dosage form suitable for administration in a capsule of size No. 1 or larger capsule.

4.1.1. The second active funds

In some embodiments, implementation of the disclosed compositions and dosage forms pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate, which may optionally contain one or more secondary active ingredients. Some combinations can function synergistically in the treatment of specific types of diseases and disorders, and conditions, and symptoms associated with such diseases or disorders. Pomalidomide or its pharmaceutically acceptable stereoisomer, prodrug, salt, MES, hydrate, or clathrate can also weaken the side effects associated with certain second active agents, and Vice versa.

Specific second active compound, which can be included in compositions and dosage forms disclosed herein vary depending on the specific readings that are subjected to treatment, prevention is the e or control.

For example, for the treatment, prevention and control of malignant disease and the second active ingredients include, but are not limited to, semaxanib; cyclosporine; etanercept; doxycycline; bortezomib; acivicin; aclarubicin; Hakodate hydrochloride; Acronis; adozelesin; aldesleukin; altretamin; ambomycin; ametantrone acetate; amsacrine; anastrozole; astromicin; asparaginase; aspirin; azacytidine; asitepu; azotomycin; batimastat; benzodepa; bikalutamid; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; breiner sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; karubitina hydrochloride; carzelesin; Cedeira; celecoxib; chlorambucil; cirolemycin; cisplatin; cladribine; cristanol mesilate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; decompletion; deazaguanine; deazaguanine mesilate; diazinon; docetaxel; doxorubicin, doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromastolone propionate; deatomizer; edatrexate; eflornithine hydrochloride; elsamitrucin; anoplate; enpromate; epirubicin; epirubicin hydrochloride; Armutalan; zorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; atopen; fadrozole hydrochlori is; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; ferritin; poquito; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubitsina hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustin; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; Matorin; maturegay; maintain; metatarsi; mitotropin; mitogillin; mitomycin; mitomycin; mitosis; mitotane; mitoxantrone hydrochloride; mycophenolate acid; nocodazole; nogalamycin; ormaplatin; oxysure; paclitaxel; pegaspargase; polymycin; pentamycin; peplomycin sulfate; perforated; pipobroman; piposulfan; piroxantrone; piroxantrone hydrochloride; plicamycin; plomelin; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; ibuprin; safingol; safingol hydrochloride; semustine; contrast; Cartosat sodium; sparsomycin; spirogermanium hydrochloride; spiramycin; spiroplatin; streptonigrin; streptozocin; alienor; talibanized; tecogen sodium; Taxotere; tegafur; telex Strona hydrochloride; ]; teniposide; teraxion; testolactone; timipre; tioguanin; thiotepa; teatterin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate the glucuronate; triptorelin; tubulosa hydrochloride; oralloy mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; wikepedia sulfate; singleseat sulfate; villarosa sulfate; vinorelbine tartrate; veneroidea sulfate; ventricina sulfate; vorozole; senility; zinostatin and zorubicin hydrochloride.

Other second means include, but are not limited to, 20-EPI-1,25-dihydrovitamin D3; 5-itinerarary; abiraterone; aclarubicin; allpole; Adelina; adozelesin; aldesleukin; antagonists ALL-TK; altretamin; ambamustine; amidax; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; Andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; entrelacs; antiparalysis morphogenetic protein-1; antiandrogen with prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; gene modulators of apoptosis; regulators of apoptosis; apurinovaya acid; Ara-CDP-DL-PTBA; deaminase arginine; Bulacan; atamestane; attemptin; akenaten 1; akenaten 2; akenaten 3; azasetron; anatoxin; asteroid; PR is spodnie baccatin III; balana; batimastat; antagonists BCR/ABL; benzocaine; benzoyltartaric; derivatives of beta-lactam beta-alamin; butaclamol In; Betulinol acid; an inhibitor of bFGF; bikalutamid; bisantrene; useridentity; bisnafide; bitrate And; bizelesin; Brevet; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin; derivatives camptothecin; capecitabine; carboxamid-amino-triazole; carboxamidates; CaRest M3; CARN 700; inhibitor derived from cartilage tissue; carzelesin; inhibitors caseinline (ICOS); castanospermine; cecropin; cetrorelix; chlorlns; chlorphenoxamine the sulfonamide; cicaprost; qi-porphyrin; cladribine; analogues clomiphene; clotrimazole; colimycin a; colimycin; combretastatin A4; similar combretastatin; convenin; kambezidis 816; Kristol; cryptophycin 8; derivatives cryptophycin a; curacin a; cyclopentadecanone; cyclopean; cephamycin; tsitarabina ocfosfate; cytolytic factor; cytostatin; daclizumab; decitabine; dehydrodidemnin; deslorelin; dexamethasone; Taxifolin; dexrazoxane; dexverapamil; diazinon; didemnin; detox; diethylnitrosamine; dihydro-5-azacytidine; 9-dihydroxy; dioxazine; diphenylpyraline; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; elastin; edelfosine; edrecolomab; aflame is in; elements; Amateur; epirubicin; epristeride; similar estramustine; agonists of estrogen; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; phenetidine; filgrastim; finasteride; flavopiridol; fileselection; fluasterone; fludarabine; fortunemagazine hydrochloride; forenames; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; Galitsin; ganirelix; inhibitors gelatinase; gemcitabine; inhibitors of glutathione; HaSulam; heregulin; hexamethyleneimine; hypericin; ibandronate acid; idarubitsin; idoxifene; Idamante; ilmofosine; ilomastat; imatinib (Gleevec®); imiqimod; peptides-Immunostimulants; inhibitor of receptor insulin-like growth factor-1; interferon agonists; interferons; interleukins; iobenguane; iododeoxyuridine; 4-ipomeanol; ireplace; irsogladine; isomerases; isohemagglutinins; fusetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; lanemile; lenograstim; lentinan sulfate; leptostachys; letrozole; leukemia inhibitory factor; leukocyte alpha-interferon; leuprolide+estrogen+progesterone; leiprorelina; levamisole; lioresal; linear analogue polyamine; lipophilic disaccharide glycosides peptide; lipophilic derivatives of platinum; lissoclinum 7; lobaplatin; lombrici; lometrexol; lonidamine; losoxantrone; lakso the bean; lurtotecan; Lutetia texaphyrin; lisofylline; lytic peptides; maytansine; sandostatin a; marimastat; misoprostol; maspin; inhibitors matrilysin; inhibitors of matrix metalloproteinases; menogaril; merbanan; peterlin; methionine; metoclopramide; inhibitor of MIF; mifepristone; miltefosine; Miramistin; mitoguazone; mitolactol; analogues of mitomycin; mitonafide; mycotoxin growth factor-saporin fibroblasts; mitoxantrone; Maarten; molgramostim; Erbitux; human chorionic gonadotropin; monophosphorylated A + cell wall of myobacteria sk; mopidamol; anticancer drug based on mustard; megaproxy; extract cell wall of mycobacteria; mylapore; N-azetidinone; N-substituted benzamide; nafarelin; agristrip; naloxone+pentazocine; nipawin; Natterer; nartograstim; nedaplatin; nemorubicin; Nejdanov acid; nilutamide; nizamettin; modulators of nitric oxide; nitroxide antioxidant; nitrolon; oblimersen (Genasense®);- 6-benzylguanine; octreotide; okizeme; oligonucleotides; onapristone; ondansetron; oracin; inducer of cytokines for oral administration; ormaplatin; asteron; oxiplatin; axiomized; paclitaxel; analogues of paclitaxel, derivatives of paclitaxel; palyulin; palmitoylation; pamidronovu acid; panaxytriol; promife; pyrabactin; panelitem; Pegasa the gas; peltatin; pentosan polysulfate sodium; pentostatin; petrosal; perflubron; perforated; perilly alcohol; fansinating; phenylacetate; inhibitors of phosphatase; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placedin a; Platin; inhibitor of plasminogen activator; a platinum complex; platinum derivatives; complex platinum-triamine; porfimer sodium; porfiromycin; prednisone; propyl-bis-acridan; prostaglandin J2; proteasome inhibitors; immunomodulator on the basis of protein A, an inhibitor of protein kinase C, inhibitors of protein kinase C; microalgal; inhibitors of protein-tyrosine-phosphatase; phosphorylase inhibitors of purine nucleosides; purpurin; pyrazoloacridine; conjugate pyridoxamine hemoglobin polyoxyethylene; antagonists raf; raltitrexed; ramosetron; inhibitors farnesyl-proteincenter ras; ras inhibitors; inhibitors of ras-GAP; reality demetilirovanny; rhenium Re-186 etidronate; rhizoxin; ribozymes; retinamide RII; rohitukine; romantic; rainmax; rubiginosa B1; robaxin; safingol; sintobin; SarCNU; sarcophyton A; sargramostim; mimetics Sdi 1; semustine; derived senescence inhibitor 1, sense oligonucleotides; inhibitors of signal transduction; sizofiran; sobuzoxane; borocaptate sodium; sodium phenylacetate; solvera; somatomedin-binding protein; sonarmen; purposeful acid; spicamycin D; puromycin; splenopathy; spongistatin 1; squalamine; stipend; inhibitors stromelysin; solifenacin; super active antagonist of vasoactive intestinal peptide; supradicto; suramin; swainsonine; tallimustine; tamoxifen-methodid; terramycin; tazarotene; tecogen sodium; tegafur; tolerability; telomerase inhibitors; ]; teniposide; tetrachlorodecaoxide; tetrasomy teleblaster; thiocoraline; thrombopoietin; mimetic of thrombopoetin; thymalfasin; agonist of the receptor of thymopoietin; timorian; thyroid stimulating hormone; atenololo adipocere; tirapazamine; titanocene bichloride; topsentin; toremifene; inhibitors broadcast; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostin; inhibitors UBC; ubenimex; inhibiting growth factor urogenital sinus; antagonists of the receptor for urokinase; vapreotide; violin; valarezo; vermin; verdini; verteporfin; vinorelbine; Wincanton; vitaxin; vorozole; sonotron; senility; salaskar and zinostatin stimulater.

One more second active means include, but are not limited to, 2-methoxyestradiol; teamstation; inducers of apoptosis of multiple myeloma cells (such as, for example, TRAIL), statins; semaxanib; cyclosporine; etanercept; doxycycline; bortezomib; oblimersen (Genasense®), Remicade; diet Xel; celecoxib; melphalan; dexamethasone (Decadron®), steroids; gemcitabine; cisplatin; temozolomide; etoposide; cyclophosphamide; temodar; carboplatin; procarbazine; gliadel; tamoxifen; topotecan; methotrexate; Arisa®; Taxol; Taxotere; fluorouracil; leucovorin; irinotecan; xeloda; CPT-11; interferon-alpha; pegylated interferon-alpha (e.g., PEG INTRON-A); capecitabine; cisplatin; thiotepa; fludarabine; carboplatin; liposomal daunorubicin; cytarabine; docetaxel; paclitaxel; vinblastine; IL-2; GM-CSF; dacarbazine; vinorelbine; zoledronic acid; palpitant; biaxin; busulfan; prednisone; biphosphonate; arsenic trioxide; vincristine; doxorubicin (Doxil®), paclitaxel, ganciclovir; adriamycin; estramustine sodium phosphate (Emcyt®); sulindac and etoposide.

In yet another embodiment, specific examples of the second means for indications intended for the treatment, prevention and control, can be found in the following sources, which are all in full included in this document for information: in U.S. patent No. 6281230 and 5635517; in the publications U.S. patent No. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142, 2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880, 2006/0122228 and 2005/0143344; and in the provisional application for U.S. patent No. 60/631870.

Examples of second active agents that can be used for the treatment, prevention and control of pain include, but are not limited to, about cnie drugs for treatment or prevention of pain, such as antidepressants; anti-convulsants; anti-hypertensive drugs; anxiety; calcium channel blockers; muscle relaxants; analgesics; opioid analgesics; anti-inflammatory drugs; COX-2 inhibitors; immunomodulators; agonists or antagonists of alpha-adrenergic receptors; immunosuppressants; corticosteroids; therapy hyperbaric oxygen; ketamine; other anesthetics; NMDA antagonists and other drugs, see, for example, in Physician''s Desk Reference, 2003. Specific examples include, but are not limited to, acetylsalicylic acid (Aspirin®); celecoxib (Celebrex®); Enbrel®; ketamine; gabapentin (Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®), oxcarbazepine (Trileptal®); valproate acid (Depakene®); morphine sulfate; hydromorphone; prednisone; griseofulvin; pentane; alendronate; difengidramin; guanethidine; Ketorolac (Acular®); thyrocalcitonin; dimethyl sulfoxide (DMSO); clonidine (Catapress®); brutily; ketanserin; reserpine; droperidol; atropine; phentolamine; bupivacaine; lidocaine; acetaminophen; nortriptyline (Pamelor®), amitriptyline (Elavil®), imipramine (Tofranil®); doxepin (Sinequan®); clomipramine (Anafranil®), fluoxetine (Prozac®), sertraline (Zoloft®); naproxen; nefazodone (Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®); bupropion (Wellbutrin®); meksiletin; nifedipine; propranolol; tramadol; lamotrigine; in the ACS; ziconotide; ketamine; dextromethorphan; benzodiazepines; baclofen; tizanidine and phenoxybenzamine.

Examples of second active agents that can be used for the treatment, control and prevention of macular degeneration and related syndromes include, but are not limited to, a steroid; a light sensitizer; integrin; an antioxidant; an interferon; a derivative of xanthine; growth hormone; neurotrophic factor; regulator of neovascularization; anti-VEGF antibody; prostaglandin; antibiotic; phytoestrogen; anti-inflammatory drug or a drug that will inhibit angiogenesis, or a combination of both. Specific examples include, but are not limited to, verteporfin; purlytin; angiostatin steroid; rhuFab; interferon-2α; pentoxifylline; adipocere tin; motexafin; Lucentis; luceti; 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidene(hydroxy)pregna-1,4-diene-3,20-dione; latanoprost (see U.S. patent No. 6225348); tetracycline and its derivatives; rifamycin and its derivatives, macrolides, metronidazole (U.S. patent No. 6218369 and 6015803); genistein; genistin; 6'-O-Mal genistin; 6'-O-Ac genistin; daidzin; 6'-O-Mal daidzin; 6'-O-Ac daidzin; glycitein; glycitin; 6'-O-Mal of glycitin; biochanin And; formononetin (U.S. patent No. 6001368); triamcinolone of acetamid; dexamethasone (U.S. patent No. 5770589); thalidomide; glutathione (U.S. patent No. 5632984); main growth factor of the fibroblast (bFGF); transform the dominant growth factor b (TGF-b); neurotrophic factor brain (BDNF); plasminogen activator factor type 2 (PAI-2); EYE101 (Eyetech Pharmaceuticals); LY333531 (Eli Lilly); miravant and implant RETISERT (Bausch&Lomb). All sources cited in this document in full is included for information.

Examples of second active agents that can be used for the treatment, prevention and control of skin diseases, include, but are not limited to, keratolytic; retinoids; α-hydroxy acid; antibiotics; collagen; botulinichesky toxins; interferon; steroids and immunomodulators. Specific examples include, but are not limited to, 5-fluorouracil; masoprocol; trichloroacetic acid; salicylic acid; lactic acid; lactate of ammonia; urea; tretinoin; isotretinoin; antibiotics; collagen; botulinichesky toxins; interferon; corticosteroids; transretinoic acid and collagen, such as placental collagen person; placental collagen animals; dermatoses; alloderm; fascia; zemetra; autologin; zyderm; Siplast; isoplast and isolagen.

Examples of second active agents that can be used for the treatment, prevention and control of pulmonary hypertension and associated disorders, include, but are not limited to, anticoagulants; diuretics; cardiac glycosides; calcium channel blockers; vasodilators; analogues of prostacyclin; endothelin antagonists is; the phosphodiesterase inhibitors (e.g., inhibitors of PDE V); inhibitors of endopeptidase; drugs that reduce blood lipids; inhibitors of thromboxane and other drugs, known to reduce pulmonary arterial pressure. Specific examples include, but are not limited to, warfarin (Coumadin®); a diuretic; cardiac glycoside; digoxin oxygen; diltiazem; nifedipine; a vasodilator such as prostacyclin (for example, prostaglandin I2 (PGI1)); epoprostenol (EPO, Floran®); treprostinil (Remodulin®); nitric oxide (NO); bosentan (Tracleer®); amlodipine; epoprostenol (Floran®); treprostinil (Remodulin®); prostacyclin; tadalafil (Cialis®)simvastatin (Zocor®); omapatrilat (Vanlev®); irbesartan (Avapro®), pravastatin (Pravachol®); digoxin; L-arginine; iloprost; butaprost and sildenafil (Viagra®).

Examples of second active agents that can be used for the treatment, prevention and control of diseases caused by exposure to asbestos include, but are not limited to, anthracyclin; platinum; an alkylating agent; oblimersen (Genasense®); this drug called cisplatin; cyclophosphamide; temodar; carboplatin; procarbazine; gliadel; tamoxifen; topotecan; methotrexate; Taxotere; irinotecan; capecitabine; cisplatin; thiotepa; fludarabine; carboplatin; liposomal daunorubicin; cytarabine; docetaxel; paclitaxel; vinblastine; IL-2; GM-CSF; dacarbazine; vinorelbine; zoledronate; Palmitoyl; biaxin; busulfan; prednisone; bisphosphonate; arsenic trioxide; vincristine; doxorubicin (Doxil®); paclitaxel; ganciclovir; adriamycin; bleomycin; hyaluronidase; pitocin C, mepacrine; thiotepa; tetracycline and gemcitabine.

Examples of second active agents that can be used for the treatment, prevention and control of parasitic diseases, include, but are not limited to, chlorin; quinine; quinidine; pyrimethamine; sulfadiazine; doxycycline; clindamycin; mefloquine; halofantrine; primaquine; hydroxychlordene; proguanil; ataque; azithromycin; suramin; pentamidine; melarsoprol; nifurtimox; amphotericin In; derivatives of pentavalent antimony (for example, stibogluconate sodium); interferon-gamma; Itraconazole; the combination killed promastigote and BCG, leucovorin; corticosteroids; sulfonamide; spiramycin; IgG (serology); trimethoprim and sulfamethoxazole.

Examples of second active agents that can be used for the treatment, prevention and control of immunodeficiency, include, but are not limited to, antibiotics (therapeutic or prophylactic uses), such as, but not limited to, ampicillin, tetracycline, penicillin, cephalosporins, streptomycin, kanamycin, and erythromycin; antivirals, such as, but not limited to, amantadine, rimantadine, acyclovir, and ribavirin; immunoglobu is n; plasma; Immunostimulants, such as levamisole and isoprinosine; biological preparations such as, not ogranichivat this, gammaglobulin, transfer factor, interleukins, and interferons; hormones such as, but not limited hormone thymic; and other immunologic agents such as, but not limited stimulators of b-cells (e.g., BAFF/BlyS), cytokines (such as IL-2, IL-4 and IL-5); growth factors (e.g., TGF-α); antibodies (e.g., anti-CD40-antibodies and IgM), oligonucleotides containing neetilirovannye CpG motifs, and vaccines (e.g., viral vaccines, and vaccines based on tumor peptides).

Examples of second active agents that can be used for the treatment, prevention and control of CNS disorders, include, but are not limited to, opioids; agonist or antagonist of dopamine, such as, but not limited to, levodopa, L-DOPA, cocaine, α-methyltyrosine, reserpine, tetrabenazine, benzotropine, pargyline, vendorama mesilate, cabergoline, pramipexole, the dihydrochloride, ropinerole, amantadine hydrochloride, selegilina hydrochloride, carbidopa, pergolid mesilate, sinemet CR and symmetrel; a MAO inhibitor, such as, but not limited to, iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor, such as, but not limited tolkapon and entacapone; a cholinesterase inhibitor, such as, but not limited physostigma is and Calicut, of physostigmine sulfate, physostigmine bromide, neostigmine bromide, neostigmine the methyl sulfate, ambenonium chloride, Adriani chloride, taken, pralidoxime chloride, obidoxime chloride, trimedoxime bromide, diacetylenes, andriani, pyridostigmine and demerary; anti-inflammatory medication, such as, without limitation, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, PEP Rho-D, mycophenolat mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamico acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, thiomalate of gold and sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone or betamethasone, and other glucocorticoids; and antiemetic drugs, such as, not limited to, metoclopramide, domperidone, p is chlorphenesin, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benchenane, batanouny, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, difenidol, dolasetron, meclizine, metallical, metopimazine, nabilone, oxybenzyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, tietilperazin, thioproperazine, tropisetron, and combinations thereof.

Examples of second active agents that can be used for the treatment, prevention and control of CNS damage and related syndromes include, but are not limited to, immunomodulators, immunosuppressants; antihypertensive drugs; anticonvulsants; fibrinolytic means; antiplatelet means; antipsychotics; antidepressants; benzodiazepines; buspirone; amantadine and other well-known and traditional medicines, which are used in patients with trauma/damage to the Central nervous system and similar syndromes. Specific examples include, but are not limited to, steroids (e.g., glucocorticoids, such as, without limitation, methylprednisolone, dexamethasone and betamethasone); anti-inflammatory medication, including, but not limited to, naproxen sodium, naproxen sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, Ketoprofen, nabumetone, rofecoxib, methotrexate, Leflunomide, sulfasalazin, gold salts, PEP Rho-D, mycophenolat mofetil, cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazin, acetaminophen, indomethacin, sulindac, mefenamico acid, meclofenamate sodium, tolmetin, Ketorolac, diclofenac, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxil, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, Amazon, zileuton, aurothioglucose, thiomalate gold and sodium, auranofin, methotrexate, colchicine, allopurinol, probenecid, sulfinpirazon and benzbromarone or betamethasone; the analogue of cAMP, including, but not ogranichivat this, db-cAMP; means, including methylphenidate, which contains l-trimethylpentyl, d-trimethylpentyl, dl-trimethylpentyl, l-eletromechanical, d-eletromechanical, dl-eletromechanical and combinations thereof; and a diuretic, such as, without limitation, mannitol, furosemide, glycerol and urea.

Examples of second active agents that can be used for the treatment, prevention and control of sleep disorders and related syndromes include, but are not limited to, tricyclic antidepressants; selective inhibitor capture Sheraton is on; anti-epileptic drugs (gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam, topiramate); antiarrhythmic agent; a blocker of sodium channels, selective inhibitor of inflammatory mediators; opioid means; second immunomodulator; combined drug and other well-known and traditional medicines that are used for the treatment of sleep. Specific examples include, but are not limited to, neurontin; oxycontin; morphine; topiramate; amitriptyline; nortriptyline; carbamazepine; l-DOPA; L-DOPA; cocaine; α-methyltyrosine; reserpine; tetrabenazine; benzotropine; pargyline; pentalpha mesilate; cabergoline; the pramipexole dihydrochloride; ropinirole; amantadine hydrochloride; selegilina hydrochloride; carbidopa; pergolid mesilate; sinemet CR; symmetrel; iproniazid; clorgyline; phenelzine and isocarboxazid; tolkapon; entacapone; physostigmine Calicut; physostigmine sulfate, physostigmine bromide; neostigmine bromide; neostigmine methyl salicylate; Ambrosina chloride; the chloride Adriani; taken; pralidoxime chloride; obidoxime chloride; trimedoxime bromide; diacetylenes; andriani; pyridostigmine and demerary; naproxen sodium; diclofenac sodium; diclofenac potassium; celecoxib; sulindac; oxaprozin; diflunisal; etodolac; meloxicam; ibuprofen; Ketoprofen; nabumetone; rofecoxib; methotrexate; Leflunomide; sulfas Latin; gold salts; PEP Rho-D; mycophenolate mofetil; cyclosporine; azathioprine; tacrolimus; basiliximab; daclizumab; salicylic acid; acetylsalicylic acid; methyl salicylate; diflunisal; salsalate; olsalazine; sulfasalazin; acetaminophen; indomethacin; sulindac; mefenamico acid; meclofenamate sodium; tolmetin; Ketorolac; diclofenac; flurbiprofen; oxaprozin; piroxicam; meloxicam; ampiroxicam; droxicam; pivoxil; tenoxicam; phenylbutazone; oxyphenbutazone; antipyrine; aminopterin; Amazon; zileuton; aurothioglucose; thiomalate gold sodium; auranofin; methotrexate; colchicine; allopurinol; probenecid; sulfinpirazon and benzbromarone or betamethasone and other glucocorticoids; metoclopramide; domperidone; prochlorperazine; promethazine; chlorpromazine; trimethobenzamide; ondansetron; granisetron; hydroxyzine; acetylation monoethanolamine; alizapride; azasetron; benchenane; batanouny; bromopride; Bulletin; clebopride; cyclizine; dimenhydrinate; difenidol; dolasetron; meclizine; metallical; metopimazine; nabilone; oxipurinol; pipamazine; scopolamine; sulpiride; tetrahydrocannabinol; tietilperazin; thioproperazine; tropisetron, and combinations thereof.

Examples of second active agents that can be used for the treatment, prevention and control of hemoglobinopathy and related disorders include, but are not limited is indeed this, interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12 and IL-18; interferons, such as interferon Alfa-2A, interferon alpha-2b, interferon Alfa-n1, interferon Alfa-n3, interferon beta-Ia, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrate or derivatives butyrate; nitric oxide; hydroxyurea; HEMOXINTM(NIPRISANTM; see U.S. patent No. 5800819); antagonists of Gardos channels, such as clotrimazole or derivatives triarylmethane; deferoxamine; protein C; and transfusion of blood or blood substitutes, such as HemospanTMor HemospanTMPS (Sangart).

4.2. The method of obtaining the dosage forms

Dosage forms disclosed herein can be prepared by any methods commonly used in pharmacy, but all methods include the stage of combining the active ingredient with the carrier which includes one or more necessary ingredients. In General, the compositions are prepared by mixing until smooth (e.g., direct) blending the active ingredient with liquid excipients or finely powdered solid fillers, or both together, and then, if necessary, giving the product the desired shape (for example, pressing, such as roller compaction). If desired, the tablets can be coated membranes using standard methods, in which the applied aqueous or non-aqueous liquid.

Dosage form disclosed herein, can be prepared by compressing or molding, optionally with one or more auxiliary ingredients. Molded tablets can be obtained by using a suitable apparatus by compressing the active ingredient in granular form, such as powder or granules, optionally mixed with a filler, above, and/or surface-active or dispersing agent. Molded tablets can be prepared by forming a mixture of the powdered compound moistened with an inert liquid diluent, in a suitable apparatus. Encapsulating dosage forms described herein can be accomplished by using capsules of methylcellulose, sodium alginate or gelatin.

In some embodiments, the implementation of active ingredients and fillers subjected to direct mixing and fill with the mixture, for example, capsules, or directly pressed into tablets. In some cases, directly mixed dosage form may be more advantageous compared to molded (e.g., obtained using roller compaction), as a direct mixing can reduce or even eliminate the negative health effects, which may be of the aerosol particles of the ingredients, the way the stories in production using extrusion.

In some cases, the composition obtained by direct mixing, can have advantages, because they require only one stage of mixing the active ingredient and excipients prior to formulation in the final dosage form, for example a tablet or capsule. This may minimize the formation of aerosol particles or dust, while for roller compaction is characterized by the formation of dust. During roller compaction extruded material is often crushed to smaller particles for further processing. During grinding can produce large quantities of aerosol particles, since the goal of this stage of production is the reduction of particle size. Then crushed material is mixed with other ingredients before preparation of the final dosage form.

For some active ingredients, in particular compounds with low solubility, particle size of the active ingredient to reduce the particle size of fine powder to increase the rate of solubilization of the active ingredient. Increasing the rate of solubilization is often necessary for the effective absorption of the active ingredient in the gastrointestinal tract. However, in order to fine powders can be subjected to direct mixing and loaded into capsules, prefer the Ino fillers should give some characteristics which makes ingredients suitable for direct blending. Examples of such characteristics include, but are not limited to, acceptable flowability. Therefore, in one embodiment, disclosed the use and compositions containing fillers, which can provide the features that make the mixture suitable for direct blending, for example, a good flowability.

4.2.1. Screening

The method of obtaining pharmaceutical compositions according to the invention preferably includes a screening of the active ingredient and excipient(s). In one embodiment, the active ingredient is sifted through a sieve with holes of approximately from 200 to 750 μm. In yet another embodiment, the active ingredient is sifted through a sieve with apertures of a size from about 200 to 400 microns. In yet another embodiment, the active ingredient is sifted through a sieve with apertures of a size from about 300 to 400 microns. Depending on the filler(s) the holes in the sieve may vary. For example, the baking powder and binder sift through holes about the size from 430 to 750 μm, from about 600 to 720 μm, or about 710 microns. Typically, the lubricant sift through smaller holes, for example, approximately from 150 to 250 μm. In one embodiment, cm, the binding substance is sifted through a sieve with holes about the size of 210 microns.

4.2.2. Pre-mixing

After sifting of filler ingredients and active ingredient are mixed in the mixer with the diffusion mechanism. In one embodiment, the mixing time is in the range from about 1 min to about 50 min, about 5 min to about 45 min, about 10 min to about 40 min, or from about 10 minutes to about 25 minutes In yet another embodiment, the mixing time is approximately 15 minutes

In that case, when using more than one filler, the fillers can be mixed in a drum mixer for about 1 min to about 20 min, or from about 5 min to about 10 min before mixing with the active ingredient.

4.2.3. Roller extrusion

In one embodiment, the pre-mixture can optionally pass through a roller press with a hammer mill, attached to the discharge mechanism of the press.

4.2.4. The final mixture

In that case, when using a lubricating substance, such as sodium fumarate, the lubricating substance is mixed with pre-mixture at the end of the method to obtain the final composition. This additional mixing is conducted for from about 1 min to about 10 min, or from about 3 minutes to about 5 minutes

4.2.5. Encapsulation

<> The mixture is then intended for formulation, encapsulate into the shell of the capsules of the desired size using, for example, apparatus for filling capsules or rotary press for making tablets.

4.3. Sets

Also provided pharmaceutical packaging or kits containing a pharmaceutical composition or dosage form disclosed herein. A sample set that contains a notice in the form prescribed by the governmental Agency regulating the manufacture, use or sale of pharmaceuticals or biological products, where this notice is allowing the organization to manufacture, use or sale for the treatment of humans.

4.4. Methods of treatment, prevention and control

Disclosed methods of treatment, prevention and/or control of certain diseases or disorders using preparative forms, compositions and/or dosage forms disclosed in this document.

Examples of diseases and disorders include, but are not limited to, cancer, disorders associated with angiogenesis, pain, including, but not limited to, complex regional pain syndrome ("CRPS"), macular degeneration (MD) and related syndromes, skin diseases, diseases caused by exposure to asbestos, parasitic diseases, immuno shall epicity, Central nervous system disorders, damage to the Central nervous system, atherosclerosis and related disorders, sleep disorder and related disorders, hemoglobinopathy and associated disorders (eg, anemia)associated with TNFα violations and other various diseases and disorders.

Examples of malignancies and pre-malignant conditions include, but are not limited to, those described in U.S. patent No. 6281230 and 5635517, Muller et al.; in various publications, U.S. patents, Zeldis, including publications 2004/A, published on 4 November 2004 (Treatment of Myelodysplastic Syndrome); 2004/A, published February 12, 2004 (Treatment of Various Types of Cancer); and 2004/0087546, published may 6, 2004 (Treatment of Myeloproliferative Diseases). Examples also include diseases that are described in the international application WO 2004/103274, published on 2 December 2004. All of these sources in full included in this document for details.

Some examples of malignant diseases include, but are not limited to, cancer: skin, such as melanoma; lymph node; breast; cervix of the uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal tract, and AIDS-related malignant disease. Compounds I which are suitable for the treatment of malignant diseases of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic and military leukemia. Compounds disclosed herein can be used for treatment, prevention or control of primary or metastatic tumors.

Other malignant diseases include, but are not limited to, malignant disease in the later stages; amyloidosis, neuroblastoma, meningioma; hemangiopericytoma; multiple metastases to the brain; glioblastoma multiforme; glioblastoma, glioma of the brain stem; a malignant brain tumor with a poor prognosis; malignant glioma; recurrent malignant glioma; anaplastic astrocytoma; anaplastic oligodendroglioma; neuroendocrine tumor; colorectal cancer with a prevalence of C&D Dukes; unresectable colorectal carcinoma; metastatic hepatocellular carcinoma; sarcoma; acute myeloid leukemia; chronic lymphocytic leukemia (CLL); Hodgkin's lymphoma; nahodkinskuju lymphoma; cutaneous T-cell lymphoma; cutaneous b-cell lymphoma; diffuse In both cell lymphoma; follicular lymphoma low-grade malignancy; metastatic melanoma (localized melanoma, including, but not limited to, ocular mesland the mu); malignant mesothelioma; malignant mesothelioma with pleural travel; peritoneal carcinoma; papillary serous carcinoma; gynecological sarcoma; soft tissue sarcoma; scleroderma; cutaneous vasculitis; Langerhans cells Langerhans; leiomyosarcoma; progressive references for additional information fibrodysplasia; insensitive to hormones malignant tumor of the prostate; resectable soft tissue sarcoma with a high risk; unresectable hepatocellular carcinoma; macroglobulinemia Waldenstrom; indolent myeloma; indolent myeloma; cancer of the fallopian tubes; androgen-independent prostate cancer; androgen-dependent non-metastatic prostate cancer to stage IV; hormone-independent prostate cancer; insensitive to chemotherapy prostate cancer; papillary carcinoma of the thyroid gland; follicular thyroid carcinoma; medullary carcinoma of the thyroid gland and leiomyoma. In a specific embodiment, a malignant tumor is metastatic. In yet another embodiment, a malignant tumor is stable or resistant to chemotherapy or radiation therapy.

In one embodiment, the diseases or disorders represent different forms of leukemia, so is e as chronic lymphocytic leukemia; chronic miliitary leukemia; acute lymphoblastic leukemia; acute myelogenous leukemia and acute myeloblastic leukemia, including, without limitation, leukemias, which are recurrent, referrername or resistant as disclosed in published U.S. patent No. 2006/0030594 published February 9, 2006, which is included in this document for details.

The term "leukemia" refers to a malignant neoplasm of blood-forming tissues. Leukemias include, but are not limited to, chronic lymphocytic leukemia; chronic miliitary leukemia; acute lymphoblastic leukemia; acute myelogenous leukemia and acute myeloblastic leukemia. Leukemia can be recurrent, Refratechnik or resistant to conventional chemotherapy. The term "recurrent" refers to cases when the patients who had remission of leukemia after therapy, occur relapse growth of leukemic cells in the bone marrow and reduce the number of normal cells in the blood. The term "refractory or resistant" refers to cases where the patients even after intensive therapy of residual leukemic cells in the bone marrow.

In another embodiment, diseases or disorders represent different types of lymphomas, including nahodkinskuju lymphoma (NHL). The term "lymphoma" refers to heterog the authorized group of neoplasms, originating from the reticuloendothelial and lymphatic systems. "NHL" refers to malignant monoclonal proliferation of lymphoid cells in the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal tract. Examples of NHL include, but are not limited to, lymphoma cells, mantle zone (MCL), lymphocytic lymphoma of intermediate degree of differentiation, intermediate lymphocytic lymphoma (ILL), diffuse subdifferentiable lymphocytic lymphoma (PDL), centrocytes lymphoma; diffuse small cell lymphoma with split cores (DSCCL); follicular lymphoma and any type of lymphoma cells, mantle zone, which can be detected under a microscope (nodular, diffuse, blast and lymphoma cells, mantle zone).

Examples of diseases and disorders associated with or characterized by, undesired angiogenesis, include, but are not limited to: inflammatory diseases; autoimmune diseases; viral diseases; hereditary diseases; allergic diseases; bacterial diseases; neovascularization eyes; the choroidal neovascularization, neovascularization of the retina and robes (neovascularization of the angle of the anterior chamber of the eye). Specific examples of diseases and disorders associated with or characterized by regulatel the NYM angiogenesis, include, but are not limited to, arthritis; endometriosis; Crohn's disease; heart failure; heart failure in the later stages of the disease; impaired renal function; groove toxins; toxic shock syndrome; osteoarthritis; retroviral infection; exhaustion; meningitis; caused by silicon dioxide fibrosis; caused by asbestos fibrosis; veterinary disease; hypercalcemia caused by cancer; stroke; circulatory shock; periodontitis; gingivitis; macrocytic anemia; refractory anemia and 5q-deletion syndrome.

Examples of pain include, but are not limited to, those described in published U.S. patent No. 2005/0203142, published September 15, 2005, which is included in this document for details. Specific examples of pain include, but are not limited to, nociceptive pain; neuropathic pain; mixed pain from nociceptive and neuropathic pain; visceral pain; migraine; headache and postoperative pain.

Examples of nociceptive pain include, but are not limited to, pain associated with chemical or thermal burns; cuts on the skin; osteoarthritis; rheumatoid arthritis; tendonitis, and myofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS type I and CRPS type II; reflex sympathetic dystrophy (RSD); reflex neurovascular dystrophy; reflex dis is rafiu; simpaticeskii persistent pain; causalgia; atrophy of the bones Sudek; algoneurodystrophy; syndrome, shoulder-hand; posttraumatic dystrophy; trigeminal neuralgia; post herpetic neuralgia; pain associated with cancer; phantom pain in the extremities; fibromyalgia; chronic fatigue syndrome; pain in spinal cord injury; Central post-stroke pain; radiculopathy; diabetic neuropathy; post-stroke pain; neuropathy with syphilis and other painful neuropathic conditions, such as caused by drugs such as vincristine and Velcade.

In the sense in which this document uses the terms "complex regional pain syndrome, CRPS and CRPS and related syndromes", they mean chronic pain syndrome characterized by one or more of the following: pain, spontaneous or induced, including allodynia (painful response to a stimulus that is not normally painful) and hyperalgesia (a strong reaction to a stimulus that is normally only slabosolenym); pain that is disproportionate to the event that caused it (for example, severe pain for many years after stretching the ankle joint)regional pain that is not limited in the course of a single peripheral nerve and Autonomous dysregulate is (for example, swelling, change in blood flow and rash)associated with trophic skin changes (abnormal growth of hair and nails and skin ulceration).

Examples of MD and related syndromes include, but are not limited to, those described in published U.S. patent No. 2004/0091455, published may 13, 2004, which is included in this document for details. Specific examples include, but are not limited to, atrophic (dry) MD; exudative (wet) MD; age-related maculopathy (ARM); the choroidal neovascularization (CNVM); detachment of the pigment epithelium of the retina (PED) and atrophy of the retinal pigment epithelial (RPE).

Examples of skin diseases include, but are not limited to, those described in published U.S. patent No. 2005/A, published on September 29, 2005, which is included in this document for details. Specific examples include, but are not limited to, keratoses and associated symptoms; skin diseases and disorders characterized by excessive growth of the epidermis; acne and wrinkles.

In the sense in which this document uses the term "keratosis", it refers to any lesion in the epidermis, characterized by limited increased growth of the stratum corneum, including, without limitation, actinic keratosis; subarray keratosis; keratoakantoma; follicular keratosis (illness Daria); inverted foul is icularly keratosis; Palmar-plantar keratoderma (PPK, keratosis of the palms and soles); keratosis eyelid and stucco keratosis. The term "actinic keratosis" also refers to senile keratosis; the senile keratosis; senile warts; senile flat warts; solar keratosis; keratoderma or keratome. The term "subarray keratosis" also refers to saboraim warts; senile warts or the basal cell papilloma. For keratosis is characterized by the following symptoms: rough appearance, scaly, erythematous papules, plaques, spicules or nodules on exposed surfaces (e.g., face, hands, ears, neck, legs and chest), overgrowth of keratin related to Horny to keratoma, hyperkeratosis, telangiectasias, elastosis, pigmented lesions, acanthosis, parakeratosis, dyskeratosis, papillomatosis, hyperpigmentation of the basal cells of the epidermis, cell cellular atypia, mitotic figures, abnormal cell adhesion, dense inflammatory infiltrates and a small percentage of squamous cell carcinomas.

Examples of skin diseases or disorders characterized by excessive growth of the epidermis, include, but are not limited to, any conditions, diseases or disorders characterized by proliferation of the epidermis, including, but not limited to, infections caused by human papilloma virus; artikelnya the keratoses; sent the m of Leser-Trelat; warty discreta (WD); pochobradsky hair (TS); the variable erythrokeratodermia (EKV); ichthyosis fruit (harlequin ichthyosis); congenital slowtest fingers; skin melanocytoma; parakeets; psoriasis; squamous cell carcinoma; confluent and reticulated papillomatosis (CRP); soft warts; horn keratome; Cowden's disease is (a syndrome of multiple hamartomas); paulley dermatosis blacks (DPN); epidermal nevus (ENS); ichthyosis vulgar; molluscum contagious; nodular prurigo and black acanthosis (AN).

Examples of lung diseases include, but are not limited to, those described in published U.S. patent No. 2005/A, published October 27, 2005, which is included in this document for details. Specific examples include, but are not limited to, pulmonary hypertension and related disorders. Examples of pulmonary hypertension and associated disorders include, but are not limited to, primary pulmonary hypertension (PPH); secondary pulmonary hypertension (SPH); family form PPH; sporadic PPH; precapillary pulmonary hypertension; hypertension (RAS); pulmonary arterial hypertension; idiopathic arterial hypertension, thrombotic pulmonary arteriopathy (TRA); plexogenic pulmonary arteriopathy; pulmonary hypertension functional class I-IV and pulmonary hypertension associated associated and the secondary dysfunction of the left ventricle; disease mitral valve; constrictive pericarditis; aortic stenosis; cardiomyopathy; mediastinal fibrosis; anomalous pulmonary venous drainage; venoocclusive lung disease; collagen vascular disease; congestive heart disease; HIV infection; exposure to drugs and toxins, such as fenfluramine; congestive heart disease; pulmonary venous hypertension, chronic obstructive pulmonary disease; interstitial lung disease; disorder of sleep-related respiratory disorders; alveolar hypoventilation is often; prolonged exposure to high altitude conditions; lung disease in newborns; alveolar-capillary dysplasia; sickle cell disease, other coagulation disorders; chronic the embolism; connective tissue disease; lupus, including systemic and cutaneous lupus erythematosus; schistosomiasis; sarcoidosis or pulmonary capillary hemangiomatosis.

Examples of diseases caused by exposure to asbestos include, but are not limited to, those described in published U.S. patent No. 2005/0100529, published may 12, 2005, which is included in this document for details. Specific examples include, but are not limited to, mesothelioma; asbestosis; malignant pleural the travel; benign pleural the travel; pleural plaques; pleural the first calcification; diffuse pleural seal; rounded atelectasis; fibrous mass and lung cancer.

Examples of parasitic diseases include, but are not limited to, those described in published U.S. patent No. 2006/0154880, published July 13, 2006, which is included in this document for details. Parasitic diseases include diseases and disorders caused by intracellular parasites of man, such as, but not limited P. falcifarium, P. ovale, P. vivax, P. malariae, L. donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana, L. braziliensis, T. gondii, B. microti, B. divergens, B. coli, C. parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S. haematobium, Trypanosoma spp., Toxoplasma ssp. and O. volvulus. Also included other diseases and disorders caused by intracellular parasites of animals, such as, but not limited to, Babesia bovis, Babesia canis, Babesia gibsoni, Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia spp. and Theileria spp. Specific examples include, but are not limited to, malaria; babesiosis; trypanosomiasis; leishmaniasis; toxoplasmosis; meningoencephalitis; keratitis; amebiasis; Giardia; cryptosporidiosis; infectious diarrheas; ciclosporin; microspores; ascariasis; trichocephalosis; hookworm; strongyles; toxocariasis; trichinosis; lymphatic filariasis; onchocerciasis; filariasis; schistosomiasis and dermatitis caused by Schistosoma parasites from animals.

Examples of immunodeficiency include, but are not limited to, those described in application for U.S. patent No. 11/28923, submitted November 30, 2005. Specific examples include, but are not limited to, failure adelaideans; deficiency of antibodies with normal or increased levels of Ig; ataxia-telangiectasia; unconfirmed lymphocytic syndrome; common variable immunodeficiency; Ig deficiency with Hyper IgM; deletions heavy chain Ig; IgA deficiency; immunodeficiency with thymoma; reticular dysgenesis; syndrome Nezelof, selective deficiency of IgG subclass; temporary hypogammaglobulinemia newborns; the syndrome Wiskott-Aldrich; X linked agammaglobulinemia; X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, those described in published U.S. patent No. 2005/0143344, published on 30 June 2005. Specific examples include, but are not limited to, amyotrophic lateral sclerosis; Alzheimer's disease; Parkinson's disease; disease Hantington; multiple sclerosis, other neuro disorders, such as Tourette's syndrome; delery; or minor disturbances in consciousness that occur within a short period of time, and amnesia, or a slight memory impairment that occurs in the absence of other disorders of the Central nervous system.

Examples of CNS damage and related syndromes include, but are not limited to, opisanie publication of U.S. patent No. 2006/0122228, published June 8, 2006, which is included in this document for details. Specific examples include, but are not limited to, damage/disorder of the Central nervous system and related syndromes, including, without limitation, primary brain damage; secondary brain injury; traumatic brain injury, focal brain damage; diffuse axonal injury; head injury; concussion; syndrome after concussion, cerebral contusion and traumatic injury; subdural hematoma; epidermal hematoma; post-traumatic epilepsy; complete SCI; incomplete SCI; acute SCI; subacute SCI; chronic SCI; syndrome of the Central part of the spinal cord; the syndrome brown-Sequard; syndrome of the anterior part of the spinal brain; the Sindh epigonus; syndrome cauda equina"; neurogenic shock, spinal shock; altered consciousness; headache; nausea; vomiting; memory loss; dizziness; blurred vision; blurred vision; emotional lability; sleep disturbances; irritability; inability to concentrate; nervousness; behavioral disorders; cognitive deficits and seizures.

Other diseases or disorders include, but are not limited to, viral, genetic, allergic, and autoimmune diseases. Specific examples include, but are not limited to, HIV and the infection; hepatitis, respiratory distress syndrome in adults; bone resorption; chronic lung diseases; dermatitis; cystic fibrosis; septic shock; endotoxic shock; hemodynamic shock; sepsis syndrome; postischemic reperfusion injury; meningitis; psoriasis; fibrosis; cachexia; syndrome graft-versus-host; graft rejection; auto-immune disease; rheumatoid spondylitis; Crohn's disease; ulcerative colitis; inflammatory bowel disease; multiple sclerosis; systemic lupus erythematosus; ENL in leprosy; the consequences of exposure; cancer; asthma or damage to the alveoli during hyperoxia.

Examples of atherosclerosis and related syndromes include, but are not limited to, those described in published U.S. patent No. 2002/0054899, published may 9, 2002. Specific examples include, but are not limited to, all forms of conditions, including atherosclerosis, including restenosis after vascular interventions, such as angioplasty; stent; atherectomy and transplantation. This document provides all kinds of interventions on vessels that take place at diseases of cardiovascular system and kidneys, such as, but not limited angioplasty of the renal vessels, percutaneous coronary intervention (PCI); percutaneous transluminal coronary angioplasty (PTCA); percutanous transluminal angioplasty of the carotid artery (PTA); the anastomosis of the coronary artery, angioplasty with stent implantation; peripheral percutaneous transluminal intervention in the iliac, femoral or popliteal arteries and surgical intervention using impregnated artificial grafts. The following table lists the major systemic arteries, which might require treatment, which are all provided in this document:

ArteryArea of the body, which it supplies blood
axillarythe shoulder and armpit
shoulderthe upper part of the hand
brachiocephalichead, neck & hand
abdominaldivides into the left gastric, splenic and hepatic artery
common carotidneck
common iliacis divided into external and internal iliac artery
coronarywhat the heart
deep femoralhip
fingerfingers
dorsal artery of the footfeet
the external carotidthe neck and the outer area of the head
external iliacfemoral artery
hiphip
stomachstomach
hepaticliver, gall bladder, pancreas and duodenum
the inferior mesentericthe descending colon, the rectum and the pelvic wall
the internal carotidneck and internal head
internal iliacrectum, bladder, genitals, buttocks, uterus and vagina
the left gastricthe esophagus and stomach
the average sakralen the I the sacrum
ovarianovaries
Palmar archhand
peronealcaviar
poplitealknee
tibiacaviar
pulmonarylight
radialforearm
renalkidney
splenicthe stomach, pancreas and spleen
subclavianshoulder
superior mesentericpancreas, small intestine, ascending and transverse colon
testiculartestes
elbowelbow

Examples of sleep disorders and related syndromes include, but are not limited to, those described in the publication PA is enta USA no 2005/022229 A1, published 6 October 2005. Specific examples include, but are not limited to, snoring during sleep; apnea during sleep; insomnia; narcolepsy; syndrome restless legs"; night fear; walking during sleep; eating during sleep; and sleep disturbances associated with chronic neurological or inflammatory diseases. Chronic neurological or inflammatory condition include, but are not limited to, complex regional pain syndrome, chronic pain in lower back; musculoskeletal pain; arthritis; radiculopathy; pain in cancer; fibromyalgia; chronic fatigue syndrome; visceral pain; pain in the bladder; chronic pancreatitis; neuropathy (diabetic, herpetic, traumatic or inflammatory); and neurodegenerative diseases such as Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis; multiple sclerosis; disease Hantington; bradykinesia; muscle rigidity; tremor in Parkinson's disease; gait in Parkinson's disease; slow movements; depression; impaired long-term memory; syndrome Rubinstein-Taybi (RTS); dementia; postural instability; hypokinetic disorders; disorders caused by senoina; Multisystem atrophy; striatonigral degeneration; olivopontocerebellar atrophy disease Shi-Drager; the motor neurone disease with symptoms of Parkinson's disease; dementia with calves Levi; Tau-pathology; progressive supranuclear palsy; corticobasal degeneration; frontotemporal dementia; amyloid disease; mild cognitive disorder; Alzheimer's disease to Parkinson's disease; Wilson's disease; disease Hallervorden-Spitze; disease Chediak-Hagashi; spinocerebellar ataxia SCA-3; X-linked dystonia; Parkinson's disease; prion disease; hyperkinetic disorder; chorea; ballism; dystonic cramps; amyotrophic lateral sclerosis (ALS); trauma to the Central nervous system and myoclonic seizures.

Examples of hemoglobinopathy and related syndromes include, but are not limited to, those described in published U.S. patent No. 2005/A, published June 30, 2005, which is included in this document for details. Specific examples include, but are not limited to, hemoglobinopathy; sickle cell anemia and other disorders associated with the differentiation of CD34+ cells.

Examples of disorders associated with TNFα, include, but are not limited to, those described in international applications WO 98/03502 and WO 98/54170, which are both included in this document for details. Specific examples include, but are not limited to, groove toxins or toxic shock syndrome; cachexia; respiratory distress syndrome in adults; bone resorption is, such as arthritis; hypercalcemia; graft versus host; cerebral malaria; inflammation; tumor growth; chronic inflammatory lung diseases; reperfusion injury; myocardial infarction; stroke; circulatory shock; rheumatoid arthritis; Crohn's disease; HIV and AIDS; other disorders such as rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; psoriatic arthritis and other forms of arthritis; septic shock; sepsis; endotoxic shock; syndrome graft-versus-host; exhaustion; Crohn's disease; ulcerative colitis; multiple sclerosis; systemic lupus erythematosus; ENL in leprosy, HIV; AIDS and opportunistic infections in AIDS; violations such as shock; sepsis; endotoxic shock; gemodinamicheski shock and sepsis syndrome; postischemic reperfusion injury; malaria; mycobacterial infections; meningitis; psoriasis; congestive heart failure; pulmonary fibrosis; cohesio; graft rejection; tumorigenic or malignant disease; asthma; autoimmune disease; the effects of exposure and damage to the alveoli as a result of hyperoxia; viral infections, for example, caused by herpes viruses; viral conjunctivitis or atopic dermatitis.

In other embodiments, the exercise also revealed the use of preparative forms HDMI the Nations and dosage forms, described herein, in various immunological applications, particularly as adjuvants for vaccines, for example, adjuvants for tumor vaccines disclosed in the publication No. 2007/0048327, published on 1 March 2007, which fully included in this document for details. These options implementation also apply to applications of compositions and preparative forms or dosage forms disclosed herein, in combination with vaccines for the treatment or prevention of cancer or infectious diseases, and other various applications, such as the reduction or desensitization of allergic reactions.

5. EXAMPLES

Embodiments of disclosed herein can be understood more fully with reference to the subsequent examples. These examples are intended to illustrate pharmaceutical compositions and dosage forms described herein, and in no way to limit.

5.1. Example 1: capsule content pomalidomide 0.5 mg

Table 1 shows the formulation of the mixture, and formulation of a single dosage form for a single dose with the content pomalidomide 0.5 mg per capsule of size No. 4.

td align="justify"> Substance
Table 1
Recipe for capsule content pomalidomide 0.5 mg
Wt.%Number
(mg/capsule)
Pomalidomide~1%0,5*
Starch 150056%35
The sodium fumarate (PRUV)~0,3%0,16
Dried spray mannitol
(Mannogem EZ)
restrest
In General100%62,5
* Indicates the number of pomalidomide corresponding to the number that provides the content pomalidomide of 0.5 mg

Pomalidomide sieved through a sieve with openings 35 mesh. Mannitol and starch individually sieved through a sieve with openings 25 mesh. Pomalidomide pre-mixed with a portion of the mannitol and starch. Preliminary mixture was sifted through a sieve with openings 0,039 inches. The remainder of mannitol and of starch was also sieved through a sieve with openings 0,039 inches. Preliminary mixture was mixed with the rest of mannitol and is ragmala. Then to this mixture was added sodium fumarate, which was sieved through a sieve with openings 60 mesh. The final mixture was encapsulated in a capsule of size No. 4.

5.2. Example 2: capsule content pomalidomide 1 mg

Table 2 shows the formulation of the mixture, and formulation of a single dosage form for a single dose with the content pomalidomide 1 mg per capsule of size No. 4.

Table 2
Recipe for capsule content pomalidomide 1 mg
SubstanceWt.%Number
(mg/capsule)
Pomalidomide~1%1*
Starch 150056%70
The sodium fumarate (PRUV)~0,3%0,32
Dried spray mannitol
(Mannogem EZ)
restrest
In General100%125
* Means the number is about pomalidomide, corresponding to the number that provides the content pomalidomide 1 mg

Pomalidomide sieved through a sieve with openings 35 mesh. Mannitol and starch individually sieved through a sieve with openings 25 mesh. Pomalidomide pre-mixed with a portion of the mannitol and starch. Preliminary mixture was sifted through a sieve with openings 0,039 inches. The remainder of mannitol and of starch was also sieved through a sieve with openings 0,039 inches. Preliminary mixture was mixed with the rest of mannitol and starch. Then to this mixture was added sodium fumarate, which was sieved through a sieve with openings 60 mesh. The final mixture was encapsulated in a capsule of size No. 4.

5.3 Example 3: capsule content pomalidomide 2 mg

Table 3 shows the formulation of the mixture, and formulation of a single dosage form for a single dose with the content pomalidomide 2 mg per capsule of size No. 2.

Pomalidomide sieved through a sieve with openings 35 mesh. Mannitol and starch individually sieved through a sieve with openings 25 mesh. Pomalidomide pre-mixed with a portion of the mannitol and starch. Preliminary mixture was sifted through a sieve with openings 0,039 inches. The remainder of mannitol and KRA is small also sifted through a sieve with openings 0,039 inches. Preliminary mixture was mixed with the rest of mannitol and starch. Then to this mixture was added sodium fumarate, which was sieved through a sieve with openings 60 mesh. The final mixture was encapsulated in a capsule of size No. 2.

5.4. Example 4: capsule content pomalidomide 3 mg

Table 4 shows the formulation of the mixture, and formulation of a single dosage form for a single dose with the content pomalidomide 3 mg per capsule of size No. 2.

Pomalidomide sieved through a sieve with openings 35 mesh. Mannitol and starch individually sieved through a sieve with openings 25 mesh. Pomalidomide pre-mixed with a portion of the mannitol and starch. Preliminary mixture was sifted through a sieve with openings 0,039 inches. The remainder of mannitol and of starch was also sieved through a sieve with openings 0,039 inches. Preliminary mixture was mixed with the rest of mannitol and starch. Then to this mixture was added sodium fumarate, which was sieved through a sieve with openings 60 mesh. The final mixture was encapsulated in a capsule of size No. 2.

5.5. Example 5: capsule content pomalidomide 4 mg

Table 5 shows the formulation of the mixture, and formulation of a single dosage form for a single dose with the contents of the SIP is lidomide 4 mg per capsule of size No. 2.

Pomalidomide sieved through a sieve with openings 35 mesh. Mannitol and starch individually sieved through a sieve with openings 25 mesh. Pomalidomide pre-mixed with a portion of the mannitol and starch. Preliminary mixture was sifted through a sieve with openings 0,039 inches. The remainder of mannitol and of starch was also sieved through a sieve with openings 0,039 inches. Preliminary mixture was mixed with the rest of mannitol and starch. Then to this mixture was added sodium fumarate, which was sieved through a sieve with openings 60 mesh. The final mixture was encapsulated in a capsule of size No. 2.

5.6. Example 6: capsule content pomalidomide 5 mg

Table 6 shows the formulation of the mixture, and formulation of a single dosage form for a single dose with the content pomalidomide 5 mg capsule of size No. 1.

Table 6
Recipe for capsule content pomalidomide 5 mg
SubstanceWt.%Number
(mg/capsule)
Pomalidomide~2%5*
Brahma is 1500 56%168
The sodium fumarate (PRUV)~0,3%0,75
Dried spray mannitol
(Mannogem EZ)
restrest
In General100%300
* Indicates the number of pomalidomide corresponding to the number that provides the content pomalidomide 5 mg

Pomalidomide sieved through a sieve with openings 35 mesh. Mannitol and starch individually sieved through a sieve with openings 25 mesh. Pomalidomide pre-mixed with a portion of the mannitol and starch. Preliminary mixture was sifted through a sieve with openings 0,039 inches. The remainder of mannitol and of starch was also sieved through a sieve with openings 0,039 inches. Preliminary mixture was mixed with the rest of mannitol and starch. Then to this mixture was added sodium fumarate, which was sieved through a sieve with openings 60 mesh. The final mixture was encapsulated in a capsule of size No. 1.

5.7. Example 7: the stability of the composition

Stability in the conditions is x accelerated aging was evaluated at 40°/75% relative humidity, and determined the content of impurities within 0; 1; 3 and 6 months. Also assessed the stability in long-term storage at 25°/60% for 0-24 months. To determine the content of impurities used gradient HPLC under the following conditions:

ColumnBond SB-CN, 150 mm × 4.6 mm internal diameter, particle size 5 µm
Temperatureroom
The mobile phaseAnd: 10/90 methanol/0.1% of triperoxonane acid
The profile of the gradientTime (min)%%
09010
59010
502080
519010
609010
Soon the TB thread 1.0 ml/min
The volume of injection box25 ál
DetectionUV, 240 nm
The analysis time60 min

The results of the experiments indicate that the content of impurities in the composition disclosed in this document, has remained at a level below the sensitivity of the method during the entire test period. The functional characteristics of the dosage form was also preserved during the entire test period. The results show that the compositions described in this document have adequate stability for clinical and other applications.

Specialists in this field, obviously, it is clear that although the herein described certain specific embodiments of, may make various changes and modifications. Such modifications are also included in the scope of the attached claims.

1. Oral dosage form in the form of a capsule containing: 1) pomalidomide in the amount of from 0.1 to 3 wt.% from the total mass of the composition; 2) a binder or filler in an amount of from 90 to 99 wt.% of the total weight of the composition, where the binder is or filler are starch, mannitol or a mixture.

2. Dosage form according to claim 1, in which pomalidomide is present in an amount of from 0.5 to 2 wt.% of the total weight of the composition.

3. Dosage form according to claim 2, in which the binder or filler is present in an amount of from 95 to 99 wt.% of the total weight of the composition.

4. Dosage form according to claim 3, in which the binder or filler is a mixture of starch and mannitol.

5. Dosage form according to claim 4, in which the starch is a pre-gelatinising starch.

6. Dosage form according to claim 4, in which mannitol is spray dried mannitol.

7. Dosage form according to claim 2, further comprising a lubricating substance in quantities of from 0.01 to 1.0 wt.% of the total weight of the composition.

8. Dosage form according to claim 7, where the lubricating substance is contained in an amount of from 0.1 to 0.5 wt.% of the total weight of the composition.

9. Dosage form according to claim 7 or 8, in which the lubricating substance is a sodium fumarate.

10. Oral dosage form in the form of a capsule, having a weight of 62.5 mg and containing: 1) pomalidomide, or its pharmaceutically acceptable salt, or MES in an amount to provide efficiency 0.5 mg pomalidomide; 2) pre-gelatinising starch in the amount of 35 mg; 3) fumarate sodium in the amount of 0.16 mg; and 4) wyssen the th spray mannitol is in the quantity which brings the total weight of the composition to 62.5 mg

11. Dosage form of claim 10, intended for insertion into the capsule of size No. 4 or larger capsule.

12. Oral dosage form with a mass of 125 mg and containing: 1) pomalidomide, or its pharmaceutically acceptable salt, or MES in the quantity, ensure the effectiveness of 1.0 mg pomalidomide; 2) pre-gelatinising starch in the amount of 70 mg; 3) fumarate sodium in the amount of 0.32 mg; and 4) spray dried mannitol is the amount that brings the total weight of the composition up to 125 mg.

13. Dosage form according to item 12, which is intended for insertion into the capsule of size No. 4 or larger capsule.

14. Oral dosage form having a weight of 250 mg and containing: 1) pomalidomide, or its pharmaceutically acceptable salt, or MES in an amount to provide efficiency 2.0 mg pomalidomide; 2) pre-gelatinising starch in the amount of 140 mg; 3) fumarate sodium in the amount of 0.64 mg; and 4) spray dried mannitol is the amount that brings the total weight of the composition up to 250 mg.

15. Dosage form by 14, which is intended for insertion into the capsule of size No. 2 or larger capsule.

16. Oral dosage form having a weight of 180 mg and containing: 1) pomalidomide, or its farmaci is almost acceptable salt, or MES in the quantity, ensure the effectiveness of 3.0 mg pomalidomide and 2) pre-gelatinising starch in amount to 100.8 mg; 3) fumarate sodium in the amount of 0.45 mg; and 4) spray dried mannitol is the amount that brings the total weight of the composition up to 180 mg

17. Dosage form according to item 16, which is intended for insertion into the capsule of size No. 2 or larger capsule.

18. Oral dosage form having a mass of 240 mg and containing: 1) pomalidomide, or its pharmaceutically acceptable salt, or MES in the quantity, ensure the effectiveness of 4.0 mg pomalidomide and 2) pre-gelatinising starch in the amount of RUR 134.4 mg; 3) sodium fumarate in an amount of 0.6 mg; and 4) spray dried mannitol is the amount that brings the total weight of the composition up to 240 mg

19. Dosage form by p intended for introduction into the capsule of size No. 2 or larger capsule.

20. Oral dosage form having a weight of 300 mg and containing: 1) pomalidomide, or its pharmaceutically acceptable salt, or MES in the quantity, ensure the effectiveness of 5.0 mg pomalidomide and 2) pre-gelatinising starch in the amount of 168 mg; 3) fumarate sodium in the amount of 0.75 mg; and 4) spray dried mannitol is the amount that Domodedovo weight of the composition up to 300 mg

21. Dosage form according to claim 20, intended for insertion into the capsule size # 1 or larger capsule.

22. The method of treatment, prevention or management of cancer pain, macular degeneration, skin diseases, lung diseases, diseases caused by exposure to asbestos, parasitic diseases, immunodeficiency diseases, disorders of the Central nervous system, CNS damage, atherosclerosis, sleep disorder, hemoglobinopathy, anemia, autoimmune diseases, viral diseases, hereditary diseases, allergic diseases, bacterial diseases, neovascularization of the eye, choroidal neovascularization, neovascularization of the retina or rubeosis, including the introduction to the patient an oral dosage form according to one of claims 1 to 21.



 

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4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention describes specific compounds, namely pyridyl-piperidine compounds, which represent antagonists of orexin receptors and can be used for treatment or prevention of neurologic and psychiatric disorders and diseases, in development of which orexin receptors participate.

EFFECT: claimed invention relates to pharmaceutical compositions, containing said compounds, as well as to application of said compounds and compositions for prevention or treatment of diseases, in development of which orexin receptors participate.

5 cl, 1 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating diabetes, obesity or metabolic syndrome, which includes therapeutically efficient amount of (5-hydroxyadamantan-2-yl)amide of trans-2'-tret-butyl-2'H-[1,3']bipyrazolyl-4'-carboxylic acid or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

EFFECT: invention also relates to application of said compound for preparation of medication, intended for treatment of said diseases.

2 cl, 1 tbl, 99 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula , where R1 denotes OH, OPO3H2 or OCOR5; R2 denotes H, OH or OPO3H2; A denotes N or CR6; R3 denotes fluorine; R4 denotes H, C1-3alkyl or C3-6cycloalkyl; R5 denotes an alanine residue; R6 denotes H, C1-6alkoxy group or halogen; and n=0 or 1; and to pharmaceutically acceptable salts of compounds of formula I. The invention also relates to a pharmaceutical composition having antibacterial activity, and to use of compounds of formula I to obtain a medicinal agent for preventing or treating bacterial infections.

EFFECT: compounds of formula I, having antibacterial activity.

14 cl, 3 dwg, 2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having chemical structure of formula II , all salts and stereoisomers thereof, where the value of radicals D, A2 and B are as described in paragraph 1 of the claim. The invention also relates to a composition having activity as a c-kit and c-fms modulator, a method of treating a subject suffering from a disease or condition mediated by c-kit and c-fms and a kit for modulating c-kit and c-fms.

EFFECT: novel compounds which can be useful in treating c-kit-mediated diseases or conditions and/or c-fms-mediated diseases or conditions are obtained and described.

21 cl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 or pharmaceutically acceptable derivatives thereof, where values of radicals X, W, R4, Ar1, Ar2, R3, R4, R20 are as described in paragraph 1 of the claim. The invention also describes a composition for treating or preventing pain, UI, ulcers, inflammatory bowel disease or irritable bowel syndrome.

EFFECT: compound which can be used in medicine is obtained and described.

46 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel compounds of general formula (I)

, where the value of each symbol is defined in the claim, which are ORL-1 receptor agonists.

EFFECT: improved bioavailability, based on improved metabolic stability, strong and high selectivity and can be used in medicine.

7 cl, 148 ex, 35 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

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