WO2006024668A1 - Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile - Google Patents
Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile Download PDFInfo
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- WO2006024668A1 WO2006024668A1 PCT/EP2005/054342 EP2005054342W WO2006024668A1 WO 2006024668 A1 WO2006024668 A1 WO 2006024668A1 EP 2005054342 W EP2005054342 W EP 2005054342W WO 2006024668 A1 WO2006024668 A1 WO 2006024668A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the hydrochloride salt of 4- [ [4-[ [4-(2-cyanoethenyl)-2,6-dimethylphenyl] amino] -2- pyrimidinyl]amino]benzonitrile and to the preparation thereof.
- WO 03/16306 discloses HIV replication inhibiting pyrimidine derivatives among which 4- [ [4-[ [4-(2-cyanoethenyl)-2,6-dimethylphenyl] amino] -2-pyrimidinyl]amino] - benzonitrile and the pharmaceutically acceptable salts thereof.
- WO 04/0162581 discloses processes to prepare 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]- benzonitrile, in particular the E-isomer, has excellent HIV replication inhibiting activity against the wild type of HIV as well as drug and multi drug resistant strains of HIV (i.e. strains which have become resistant to art-known drug(s)).
- the compound has thus potential to be a good candidate for the development of a medicament for the treatment of HIV infection.
- a good drug candidate should preferably also be stable chemically as well as physically; should have an acceptable toxicity profile; should have an acceptable bioavailability.
- the bioavailability of the compound influences the dose of the compound required for administration in order to reach a therapeutically effective concentration of the compound in the patient.
- Compounds having a low bioavailability need to be administered in higher doses compared to compounds having a higher bioavailability.
- Possible consequences of the need for higher doses may comprise : an increased risk to adverse effects; an increase in the size of the dosage form; an increase in the frequency of administration. These factors may influence adherence to antiretroviral therapy. Therapy adherence is one of the most important factors influencing the effectiveness of HIV treatment. Increase in dosing frequency and increase in pill size may lead to reduced therapy adherence and hence reduced therapy effectiveness.
- bioavailability of a compound intended to be administered orally is dependent on the compounds solubility in water as well as the compounds permeability (its ability to be absorbed across the intestinal membrane).
- BCS Biopharmaceutics Classification System
- Class 2 Low Solubility - High Permeability
- Class 3 High Solubility - Low Permeability
- Class 4 Low Solubility - Low Permeability
- Compounds with a low solubility or a low permeability may suffer from a low bioavailability when administered orally.
- Free base 4- [ [4- [ [4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino] -2-pyrimidinyl] amino]benzonitrile can be classified as a BCS class 2 compound and has thus a low solubility in water.
- 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile does not only exhibit a low solubility in water, but also in an acidic environment. Consequently, when administered orally in a conventional solid dosage form, a low bioavailability may be expected.
- the prepared salts appeared to have only a slight improved solubility in water and in HCl.
- the prepared salts still belong to BCS class 2. Thus, also for the prepared salts a low bioavailability could be expected.
- the hydrochloride salt of 4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, in particular its E-isomer, has a significant improved in vivo bioavailability compared to the free base.
- the present salt administered as a solid dosage form has an in vivo bioavailability which is comparable with the bioavailability of the free base administered as an oral PEG 400 solution.
- the hydrochloride salt may be formulated without the need of complex formulation techniques.
- the hydrochloride salt of the present invention was also found to be non-hygroscopic and to be chemically and physically stable in different conditions of humidity and temperatures.
- Figure 1 is an IR spectrum of polymorphic Form A of (E) 4-[[4-[[4-(2-cyanoethenyl)- 2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- Figure 2 is X-ray powder diffraction pattern of polymorphic Form A of (E) 4-[[4-[[4- (2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- HCl X-ray powder diffraction pattern of polymorphic Form A of (E) 4-[[4-[[4- (2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- Figure 3 is an IR spectrum of the dry state of polymorphic Form B of (E) 4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- HCl Figure 4 is X-ray powder diffraction pattern of the dry state of polymorphic Form B of (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile.
- HCl X-ray powder diffraction pattern of the dry state of polymorphic Form B of (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile.
- Figure 5 is an IR spectrum of polymorphic Form C of (E) 4-[[4-[[4-(2-cyanoethenyl)- 2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- HCl Figure 6 is X-ray powder diffraction pattern of polymorphic Form C of (E) 4-[[4-[[4- (2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- HCl X-ray powder diffraction pattern of polymorphic Form C of (E) 4-[[4-[[4- (2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- Figure 7 is an IR spectrum of pseudopolymorphic Form D of (E) 4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- E 4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.
- Figure 8 is X-ray powder diffraction pattern of pseudopolymorphic Form D of (E) A-
- the present invention relates to the hydrochloride (HCl) salt of 4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, a iV-oxide or a stereochemically isomeric form thereof.
- the present invention relates in particular to a compound of formula (I)
- iV-oxide forms of the present compound of formula (I) are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called iV-oxide.
- stereochemically isomeric forms as used hereinbefore defines all the possible stereoisomeric forms which the compound of formula (I), and the iV-oxides may possess. Unless otherwise mentioned or indicated, the chemical designation of the compound denotes the mixture of all possible stereochemically isomeric forms as well as each of the individual isomeric forms of the compound of formula (I) and the iV-oxides thereof substantially free of the other isomers. Stereochemically isomeric forms of the compound of formula (I) are obviously intended to be embraced within the scope of this invention.
- the compound of formula (I) may exist in 2 stereochemical configurations at the double bond of the cyanoethenyl chain, i.e. the E (Entadel) configuration (E-isomer) and the Z (Zusammen) configuration (Z isomer).
- E and Z are well known to a person skilled in the art.
- a particular embodiment of the compound of formula (I) is the E-isomer, i.e. a
- Another particular embodiment of the compound of formula (I) is the Z- isomer, i.e. a compound of formula (I-b)
- the pure E-isomer or any isomeric mixture of the E- and the Z- isomers wherein the E-isomer is predominantly present is meant, i.e. an isomeric mixture containing more than 50% or in particular more than 80% of the E-isomer, or even more in particular more than 90% of the E-isomer.
- the E-isomer substantially free of the Z- isomer refers to E-Z-mixtures with no or almost no Z-isomer, e.g. isomeric mixtures containing as much as 90%, in particular 95% or even 98% or 99% of the E- isomer.
- the pure Z-isomer or any isomeric mixture of the Z- and the E-isomers wherein the Z-isomer is predominantly present is meant, i.e. an isomeric mixture containing more than 50% or in particular more than 80% of the Z-isomer, or even more in particular more than 90% of the Z-isomer.
- the Z-isomer substantially free of the E-isomer refers to E-Z-mixtures with no or almost no E-isomer, e.g. isomeric mixtures containing as much as 90%, in particular 95% or even 98% or 99% of the Z- isomer.
- Polymorphic forms of the present salts also fall within the ambit of the present invention.
- Polymorphic forms of pharmaceutical compounds may be of interest to those involved in the development of a suitable dosage form because if the polymorphic form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next.
- a pharmaceutical compound is produced for use, it is important to recognize the polymorphic form delivered in each dosage form to assure that the production process use the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to assure that either a single polymorphic form or some known combination of polymorphic forms is present.
- certain polymorphic forms may exhibit enhanced thermodynamic stability and may be more suitable than other polymorpholic forms for inclusion in pharmaceutical formulations.
- a polymorphic form of a compound of the invention is the same chemical entity, but in a different crystalline arrangement.
- Solvent addition forms which the salts of the present invention are able to form also fall within the ambit of the present invention. Examples of such forms are e.g. hydrates, alcoholates and the like. Solvates are herein also referred to as pseudopolymorphic forms. Preferred is an anhydric salt.
- a particular embodiment of the present invention is a particular polymorphic or pseudopolymorphic form of a compound of formula (I-a), i.e. (E) 4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile.HCl.
- a first particular polymorphic form of the compound of formula (I-a) is herein designated as Form A (see Figure 1 and 2).
- Form B A second particular form of the compound of formula (I-a) is herein designated as Form B.
- Form B can be present in two states, a dry state (polymorphic form) and a wetted state (pseudopolymorphic form). Only the characteristics of form B in the dry state are given (see Figure 3 and 4).
- a third particular polymorphic form of the compound of formula (I-a) is herein designated as Form C (see Figure 5 and 6).
- a fourth particular pseudopolymorphic form of the compound of formula (I-a) is herein designated as Form D (see Figure 7 and 8).
- a preferred polymorphic form of the compound of formula (I-a) is Form A.
- the term "compound of formula (I), (I-a) or (I-b)" is meant to also include the iV-oxide forms, the stereochemically isomeric forms and the polymorphic or pseudopolymorphic forms. Of special interest is a stereochemically pure form of the compound of formula (I).
- a preferred compound of formula (I) is a compound of formula (I-a).
- the compounds of formula (I), (I-a) or (I-b) can be prepared by reacting the corresponding free base with hydrochloric acid (HCl) in the presence of a suitable solvent, such as for example a suitable acid, e.g. acetic acid.
- a suitable solvent such as for example a suitable acid, e.g. acetic acid.
- the compounds of formula (I), (I-a) or (I-b) have antiretroviral activity. They are able to inhibit the replication of HIV, in particular HIV-I.
- HIV Human Immunodeficiency Virus
- AIDS Acquired Immune Deficiency Syndrome
- the HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system.
- an infected patient has an ever decreasing number of T-4 cells, which moreover behave abnormally.
- the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers.
- HIV infection Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
- PDL progressive generalized lymphadenopathy
- ARC AIDS-related complex
- the present compounds also show activity against drug and multidrug resistant HIV strains, in particular drug and multidrug resistant HIV-I strains, more in particular the present compounds show activity against HIV strains, especially HIV-I strains, that have acquired resistance to one or more art-known non-nucleoside reverse transcriptase inhibitors.
- Art-known non-nucleoside reverse transcriptase inhibitors are those non- nucleoside reverse transcriptase inhibitors other than the present compounds and in particular commercial non-nucleoside reverse transcriptase inhibitors.
- the HIV replication inhibiting activity of 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile is described in WO 03/16306, which is incorporated herein by reference. Due to their antiretroviral properties, particularly their anti-HIV properties, especially their HIV-I replication inhibiting activity, the present compounds are useful in the treatment of individuals infected by HIV and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded mammals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase.
- Conditions which may be prevented or treated with the compounds of the present invention include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic Central Nervous System diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis Therefore, the compounds of formula (I), (I-a) or (I-b) can be used as a medicine.
- the compounds of the present invention may therefore be used as medicines against above-mentioned conditions.
- Said use as a medicine or method of treatment comprises the administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-I.
- the present compounds may be used in the manufacture of a medicament for the treatment or the prevention of HIV infection, preferably for the treatment of HIV infection.
- a method of treating mammals, including humans, suffering from or a method of preventing warm- blooded mammals, including humans, to suffer from viral infections, especially HIV infections comprises the administration, preferably oral administration, of an effective amount of a salt of the present invention to mammals including humans.
- therapeutic effective plasma levels may be obtained by administering a pharmaceutical composition comprising a lower amount of the salt compared to what would be needed of the corresponding free base.
- the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b).
- the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain both emtricitabine and tenofovir diisoproxyl fumarate.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
- compositions for administration purposes.
- compositions there may be cited all compositions usually employed for systemically administering drugs.
- an effective amount of the compound of formula (I), (I-a) or (I-b) as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
- These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally.
- any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are obviously employed.
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
- the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
- Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
- These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
- the salts of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
- the salts of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
- the compounds of the present invention may also be topically administered in the form of drops, in particular eye drops.
- Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
- WO 2004/069812 which is incorporated herein by reference, describes the ability of pyrimidine derivatives among which 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]- amino]-2-pyrimidinyl]amino]benzonitrile and pharmaceutically acceptable salts thereof, to prevent HIV infection via sexual intercourse or related intimate contact between partners.
- the present invention also relates to a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b).
- a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain both emtricitabine and tenofovir diisoproxyl fumarate.
- the present invention also relates to a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
- a pharmaceutical composition in a form adapted to be applied to a site where sexual intercourse or related intimate contact can take place, such as the genitals, rectum, mouth, hands, lower abdomen, upper thighs, especially the vagina and mouth, comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcripta
- compositions usually employed for being applied to the vagina, rectum, mouth and skin such as for example gels, jellies, creams, ointments, films, sponges, foams, intravaginal rings, cervical caps, suppositories for rectal or vaginal application, vaginal or rectal or buccal tablets, mouthwashes.
- a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of administration.
- bioadhesive in particular a bioadhesive polymer.
- a bioadhesive may be defined as a material that adheres to a live biological surface such as for example a mucus membrane or skin tissue.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) characterized in that the pharmaceutical composition is bioadhesive to the site of application.
- the site of application is the vagina, rectum, mouth or skin, most preferred is the vagina.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) characterized in that the pharmaceutical composition is bioadhesive to the site of application provided that the composition does not contain both emtricitabine and tenofovir diisoproxyl fumarate.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient an effective amount of a compound of formula (I), (I-a) or (I-b) characterized in that the pharmaceutical composition is bioadhesive to the site of application provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
- Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
- the exact dosage and frequency of administration depends on the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- compositions of the present invention can be administered at any time of the day independently of the food taken in by the subject.
- the present compositions are administered to fed subjects.
- An interesting embodiment of the present invention concerns an oral pharmaceutical composition, i.e. a pharmaceutical composition suitable for oral administration, comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b).
- the present invention concerns an oral pharmaceutical composition, i.e.
- a pharmaceutical composition suitable for oral administration comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain both emtricitabine and tenofovir diisoproxyl fumarate, more in particular a pharmaceutical composition suitable for oral administration, comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) provided that the composition does not contain one or more nucleoside reverse transcriptase inhibitors and/or one or more nucleotide reverse transcriptase inhibitors.
- the oral pharmaceutical composition is a solid oral pharmaceutical composition, more in particular a tablet or a capsule, even more in particular a tablet.
- a tablet according to the present invention may be formulated as a once daily tablet.
- the pharmaceutical compositions of the present invention contain those quantities of a compound of formula (I), (I-a) or (I-b) equivalent to from about 5 to about 500 mg of the corresponding free base 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, its E or Z isomer, more preferably from about 10 mg to about 250 mg of the corresponding free base, even more preferably from about 20 mg to about 200 mg of the corresponding free base.
- the present pharmaceutical compositions contain those quantities of a compound of formula (I), (I-a) or (I-b) equivalent to 25 mg, 50 mg, 75 mg, 100 mg or 150 mg of the corresponding free base (base equivalent).
- x means, for example, x ⁇ 10 %.
- the particle size of the compound of formula (I), (I-a) or (I-b) preferably is less than 50 ⁇ m, more preferably less than 25 ⁇ m, even more preferably less than 20 ⁇ m. Further preferred is a particle size of about 15 ⁇ m or less, or about 12 ⁇ m or less, or about 10 ⁇ m or less, or about 5 ⁇ m or less. Most preferably, the particle size ranges between about 0.2 and about 15 ⁇ m or between about 0.2 and about 10 ⁇ m.
- compositions of the present invention preferably comprise a wetting agent.
- wetting agent in the compositions of the invention there may be used any of the physiologically tolerable wetting agent suitable for use in a pharmaceutical composition.
- a wetting agent is an amphiphilic compound; it contains polar, hydrophilic moieties as well as non-polar, hydrophobic moieties.
- hydrophilic or hydrophobic are relative terms.
- the relative hydrophilicity or hydrophobicity of a wetting agent may be expressed by its hydrophilic-lipophilic balance value ("HLB value).
- HLB value hydrophilic-lipophilic balance value
- Wetting agents with a lower HLB value are catagorized as being "hydrophobic" wetting agents whereas wetting agents with a higher HLB value are catagorized as being “hydrophilic” wetting agents.
- wetting agents having a HLB value greater than about 10 are generally considered as being hydrophilic wetting agents; wetting agents having a HLB value lower than about 10 are generally considered as being hydrophobic wetting agents.
- the present compositions preferably comprise a hydrophilic wetting agent.
- HLB value of a wetting agent is only a rough guide to indicate the hydrophilicity/hydrophobicity of a wetting agent.
- the HLB value of a particular wetting agent may vary depending upon the method used to determine the HLB value; may vary depending on its commercial source; is subject to batch to batch variability.
- a person skilled in the art can readily identify hydrophilic wetting agents suitable for use in the pharmaceutical compositions of the present invention.
- the wetting agent of the present invention can be an anionic, a cationic, a zwitterionic or a non-ionic wetting agent, the latter being preferred.
- the wetting agent of the present invention can also be a mixture of two or more wetting agents.
- Suitable wetting agents for use in the compositions of the present invention are listed below. It should be emphasized that said list of wetting agents is only illustrative, representative and not exhaustive. Thus the invention is not limited to the wetting agents listed below. In the present compositions, also mixtures of wetting agents may be used.
- Suitable wetting agents which may be used in the present invention comprise : a) Polyethylene glycol fatty acid monoesters comprising esters of lauric acid, oleic acid, stearic acid, ricinoic acid and the like with PEG 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400, 600 and the like, for instance PEG-6 laurate or stearate, PEG-7 oleate or laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate or stearate, PEG-10 laurate or oleate or stearate, PEG- 12 laurate or oleate or stearate or ricinoleate, PEG- 15 stearate or oleate, PEG-20 laurate or oleate or stearate, PEG-25 stearate, PEG-32 laurate or oleate or stearate, PEG-30
- corn oil olive oil, peanut oil, palm kernel oil, apricot kernel oil, almond oil and the like, such as PEG-20 castor oil or hydrogenated castor oil or corn glycerides or almond glycerides, PEG-23 castor oil , PEG-25 hydrogenated castor oil or trioleate, PEG-35 castor oil, PEG-30 castor oil or hydrogenated castor oil, PEG-38 castor oil, PEG-40 castor oil or hydrogenated castor oil or palm kernel oil, PEG-45 hydrogenated castor oil, PEG-50 castor oil or hydrogenated castor oil, PEG-56 castor oil, PEG-60 castor oil or hydrogenated castor oil or corn glycerides or almond glycerides, PEG- 80 hydrogenated castor oil, PEG-100 castor oil or hydrogenated castor oil, PEG-200 castor oil, PEG- 8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, lauroyl macrogol-32 gly
- Polyethylene glycol sorbitan fatty acid esters such as for example PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate or sorbitan tristearate or sorbitan monooleate or sorbitan trioleate or sorbitan monoisostearate or sorbitan monopalmiate or sorbitan monostearate, PEG-4 sorbitan monolaurate, PEG-5 sorbitan monooleate, PEG-6 sorbitan monooleate or sorbitan monolaurate or sorbitan monostearate, PEG-8 sorbitan monostearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan oleate or sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-80 sorbitan monolaurate, PEG sorbitol hexaoleate (Atlas G- 1086) and
- succinylated monoglycerides sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters of mono-and diglycerides, citric acid esters of mono-and diglycerides, glyceryl- lacto esters of fatty acids, lactylic esters of fatty acids, calcium/sodium stearoyl-2-lactylate, calcium/sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ether carboxylates and the like; such as sulfates and sulfonates e.g.
- alkyl sulfates ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, octyl sulfosuccinate disodium, disodium undecyleneamido-MEA-sulfosuccinate and the like; such as cationic wetting agents e.g.
- hexadecyl triammonium bromide decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (lauryl betaine), ethoxylated amines (polyoxyethylene-15 coconut amine) and the like.
- PEG-20 oleyl ether or cetyl ether or stearyl ether this means that PEG- 20 oleyl ether and PEG-20 cetyl ether and PEG-20 stearyl ether are intended.
- PEG-20 castor oil or hydrogenated castor oil or corn glycerides or almond glycerides has to be read as PEG-20 castor oil and PEG-20 hydrogenated castor oil and PEG-20 corn glycerides and PEG-20 almond glycerides.
- Preferred wetting agents in the present compositions are sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or those wetting agents belonging to the group of the polyethylene glycol sorbitan fatty acid esters, such as wetting agents known as Tween, e.g. Tween 20, 60, 80. Most preferred, the wetting agent is Tween 20.
- the wetting agent is preferably present at a concentration from about 0.01 to about 5% by weight relative to the total weight of the composition, preferably from about 0.1 to about 3 % by weight, more preferably from about 0.1 to about 1 % by weight.
- the quantity of wetting agent used in the present compositions may depend on the amount of the compound of formula (I), (I-a) or (I-b) present in the composition or on the particle size of the compound of formula (I), (I-a) or (I-b). A higher amount or a smaller particle size may require more wetting agent.
- composition may also further contain an organic polymer.
- the organic polymer may be used as a binder during the manufacture of the composition.
- the organic polymer used in the compositions of the invention may be any of the physiologically tolerable water soluble synthetic, semi-synthetic or non-synthetic organic polymers.
- the polymer may be a natural polymer such as a polysaccharide or polypeptide or a derivative thereof, or a synthetic polymer such as a polyalkylene oxide (e.g. PEG), polyacrylate, polyvinylpyrrolidone, etc.
- a polyalkylene oxide e.g. PEG
- polyacrylate e.g. polyacrylate
- polyvinylpyrrolidone e.g. polyvinylpyrrolidone
- Mixed polymers e.g. block copolymers and glycopeptides may of course also be used.
- the polymer conveniently has a molecular weight in the range 500D to 2 MD, and conveniently has an apparent viscosity of 1 to 15,000 mPa.s when in a 2% aqueous solution at 20°C.
- the water-soluble polymer can be selected from the group comprising - alkylcelluloses such as methylcellulose,
- hydroxyakylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose,
- - hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose (e.g. HPMC 2910 15 mPa.s; HPMC 2910 5 mPa.s), - carboxyalkylcelluloses such as carboxymethylcellulose,
- carboxyalkylcelluloses such as sodium carboxymethylcellulose
- carboxyalkylalkylcelluloses such as carboxymethylethylcellulose
- starches such as starch 1551, - pectins such as sodium carboxymethylamylopectin,
- polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabic, guargum and xanthan gum,
- Non-enumerated polymers which are pharmaceutically acceptable and have appropriate physico-chemical properties as defined hereinbefore are equally suited for preparing compositions according to the present invention.
- the organic polymer is starch, polyvinylpyrrolidone or a cellulose ether, e.g. PVP K29-32, PVP K90, methyl cellulose, hydroxypropylcellulose, hydroxyethyl methylcellulose, or hydroxypropyl methylcellulose (HPMC).
- PVP K29-32 polyvinylpyrrolidone
- PVP K90 methyl cellulose
- HPMC hydroxypropyl methylcellulose
- HPMC contains sufficient hydroxypropyl and methoxy groups to render it water- soluble.
- HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble.
- Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule.
- Hydroxy- propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
- a preferred HPMC is hypromellose 2910 15 mPa.s or hypromellose 2910 5mPa.s, especially hypromellose 2910 15 mPa.s.
- Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435).
- the first two digits represent the approximate percentage of methoxyl groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups ; 15 mPa.s or 5 mPa.s is a value indicative of the apparent viscosity of a 2 % aqueous solution at 20°C.
- the organic polymer may conveniently be present up to about 10% by weight, preferably from about 0.1 to about 5%, more preferably from about 0.5 to about 3% by weight (relative to the total weight of the composition).
- composition may also further contain a diluent and/or a glidant.
- Pharmaceutical acceptable diluents comprise calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactitol, lactose anhydrous, lactose monohydrate, mannitol, sorbitol, starch, pregelatinized starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray- dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), commercially available as Microcelac ® , a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2), commercially available as Prosolv ® .
- Preferred is lactose monohydrate, microcrystalline cellulose or silicified microcrystalline cellulose.
- glidants comprise talc, colloidal silicon dioxide, starch. magnesium stearate. Preferred is colloidal silicon dioxide.
- the composition may also further comprise a disintegrant and a lubricant.
- Pharmaceutically acceptable disintegrants comprise starch, ion exchange resins, e.g. Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gum, e.g. croscarmellose sodium (e.g. Ac-di-Sol ® ), sodium starch glycollate, sodium carboxymethylcellulose, sodium dodecyl sulphate, modified corn starch, microcrystalline cellulose, magnesium aluminium silicate, alginic acid, alginate, powdered cellulose.
- ion exchange resins e.g. Amberlite, cross-linked polyvinylpyrrolidone
- modified cellulose gum e.g. croscarmellose sodium (e.g. Ac-di-Sol ® )
- sodium starch glycollate sodium carboxymethylcellulose
- sodium dodecyl sulphate modified corn starch
- microcrystalline cellulose microcrystalline cellulose
- magnesium aluminium silicate alginic acid, alginate, powdered cellulose.
- Pharmaceutically acceptable lubricants comprise magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulphate.
- Tablets of the present invention may in addition include other optional excipients such as, for example, flavors, sweeteners and colors.
- Solid pharmaceutical compositions according to the present invention may comprise by weight based on the total weight of the composition :
- Tablets according to the present invention may comprise by weight based on the total weight of the tablet core : (a) from 5 to 50% of a compound of formula (I), (I-a) or (I-b);
- Tablets of the present invention may optionally be film-coated following art-known coating procedures. Film-coated tablets are easier to swallow than uncoated tablet cores, are usually easier to distinguish from other tablets - in particular when the film- coat contains a dye or a pigment -, may have reduced tackiness, and may furthermore have an improved stability (increased shelf- life), e.g. because the coating may protect the active ingredient from the influence of light.
- the film coat is an immediate release coat.
- Film coatings may comprise a film- forming polymer and optionally a plasticizer or a pigment.
- An example of a suitable film- forming polymer is hydroxypropyl methylcellulose, and an example of a suitable plasticizer is polyethyleneglycol, e.g.
- the film coating is a non-transparant film coating.
- An example of a suitable coating is Opadry ® , in particular coating powder Opadry ® II White.
- Tablets of the present invention can be prepared by direct compression or wet granulation.
- the present invention is also concerned with a process of preparing a tablet comprising a compound of formula (I), (I-a) or (I-b) comprising the steps of :
- step (i) dry blending the active ingredient, the disintegrant and the optional glidant with the diluent; (ii) optionally mixing the lubricant with the mixture obtained in step (i);
- step (iii) compressing the mixture obtained in step (i) or in step (ii) in the dry state into a tablet
- step (iv) optionally film-coating the tablet obtained in step (iii).
- the present invention is also concerned with a process of preparing a tablet comprising a compound of formula (I), (I-a) or (I-b) comprising the steps of : (i) dry blending the active ingredient and part of the diluent; (ii) preparing a binder solution by dissolving the binder and the wetting agent in the binder solution solvent;
- step (iii) spraying the binder solution obtained in step (ii) on the mixture obtained in step (i); (iv) drying the wet powder obtained in step (iii) followed by sieving and optionally mixing;
- step (v) mixing the remaining part of the diluent, the disintegrant and the optional glidant in the mixture obtained in step (iv);
- step (vi) optionally adding the lubricant to the mixture obtained in step (v); (vii) compressing the mixture obtained in step (vi) into a tablet; (viii) optionally film-coating the tablet obtained in step (vii).
- the present compound of formula (I), (I-a) or (I-b) can be used alone or in combination with other therapeutic agents, such as anti-virals, antibiotics, immunomodulators or vaccines for the treatment of viral infections. They may also be used alone or in combination with other prophylactic agents for the prevention of viral infections.
- the present compounds may be used in vaccines and methods for protecting individuals against viral infections over an extended period of time.
- the compounds may be employed in such vaccines either alone or together with other anti- viral agents in a manner consistent with the conventional utilization of reverse transcriptase inhibitors in vaccines.
- the present compounds may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against HIV infection.
- the combination of an antiretroviral compound and a compound of formula (I), (I-a) or (I-b) can be used as a medicine.
- the present invention also relates to a product containing (a) a compound of formula (I), (I-a) or (I-b), and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment.
- the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) and (b) one or more other antiretroviral agents.
- the invention also relates to a product containing (a) a compound of formula (I), (I-a) or (I-b), and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment provided that the composition does not contain both emtricitabine and tenofovir diisoproxyl fumarate.
- the invention also relates to a product containing (a) a compound of formula (I), (I-a) or (I-b), and (b) one or more other antiretroviral compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment provided that the one or more other antiretroviral compounds are other than nucleoside reverse transcriptase inhibitors and/or nucleotide reverse transcriptase inhibitors.
- the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) and (b) one or more other antiretroviral agents.
- the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) and (b) one or more other antiretroviral agents provided that the composition does not contain both emtricitabine and tenofovir diisoproxyl fumarate. .
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (a) a therapeutically effective amount of a compound of formula (I), (I-a) or (I-b) and (b) one or more other antiretroviral agents provided that the one or more other antiretroviral compounds are other than nucleoside reverse transcriptase inhibitors and/or nucleotide reverse transcriptase inhibitors.
- Said other antiretroviral compounds may be known antiretroviral compounds such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate); nucleoside reverse transcriptase inhibitors, e.g.
- zidovudine (3'-azido-3'-deoxythymidine, AZT), didanosine (2',3'-dideoxyinosine; ddl), zalcitabine (dideoxycytidine, ddC) or lamivudine (2'-3'-dideoxy-3'-thiacytidine, 3TC), stavudine (2',3'-didehydro-3'-deoxythymidine, d4T), abacavir, abacavir sulfate, emtricitabine ((-) FTC), racemic FTC and the like; non-nucleoside reverse transcriptase inhibitors such as nevirapine (11-cyclopropyl- 5,l l-dihydro-4-methyl-6H-dipyrido-[3,2-b : 2',3'-e][l,4]diazepin-6-one), efavirenz, delavirdine, T
- RO-5-3335, or REV inhibitors and the like; protease inhibitors e.g. indinavir, ritonavir, saquinavir, lopinavir (ABT-378), nelfinavir, amprenavir, TMC-114, BMS-232632, VX- 175 and the like; fusion inhibitors, e.g. T-20, T- 1249 and the like; CXCR4 receptor antagonists, e.g. AMD-3100 and the like; inhibitors of the viral integrase; nucleotide- like reverse transcriptase inhibitors, e.g.
- tenofovir tenofovir diphosphate, tenofovir disoproxil fumarate and the like
- ribonucleotide reductase inhibitors e.g. hydroxyurea and the like
- CCR5 antagonists e.g. ancriviroc, aplaviroc hydrochloride, vicriviroc.
- Combination therapies as described above exert a synergistic effect in inhibiting ⁇ IV replication because each component of the combination acts on a different site of ⁇ IV replication.
- the use of such combinations may reduce the dosage of a given conventional anti-retro viral agent which would be required for a desired therapeutic or prophylactic effect as compared to when that agent is administered as a monotherapy.
- These combinations may reduce or eliminate the side effects of conventional single anti-retro viral therapy while not interfering with the anti- viral activity of the agents.
- These combinations reduce potential of resistance to single agent therapies, while minimizing any associated toxicity.
- These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity.
- the compounds of the present invention may also be administered in combination with immunomodulating agents, e.g. levamisole, bropirimine, anti-human alpha interferon antibody, interferon alpha, interleukin 2, methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor, naltrexone and the like; antibiotics, e.g. pentamidine isethiorate and the like; cholinergic agents, e.g. tacrine, rivastigmine, donepezil, galantamine and the like; NMDA channel blockers, e.g. memantine to prevent or combat infection and diseases or symptoms of diseases associated with ⁇ IV infections, such as AIDS and ARC, e.g. dementia.
- immunomodulating agents e.g. levamisole, bropirimine, anti-human alpha interferon antibody, interferon alpha, interleukin 2, methionine enkephalin, diethyldithio
- the compound to be analyzed was mixed with alkali halide and pressed to a pellet (Ph.
- X-ray powder diffraction (XRPD) analyses were carried out on a Philips X'PertPRO MPD diffractometer PW3050/60 with generator PW3040. The instrument is equipped with a Cu LFF X-ray tube PW3373/00.
- the compound to be analyzed was spread on a zero background sample holder.
- Soller slit 0.04 rad
- Soller slit 0.04 rad
- Form A is characterized by an FTIR spectrum with typical absorption bands at about 2217, 1652, 1497, 1435, 1338, 1199 and 550 cm “1 . Additional absorption bands are observed at 1631, 1596, 1537, 1504, 1249, 1214, 1179 , 1152 and 1070 cm “1 . (See Figure 1).
- Form A is characterized by typical diffraction peaks at two-theta positions 9.7° ⁇ 0.2°, 13.5° ⁇ 0.2° and 15.0° ⁇ 0.2°.
- Form A is further characterized by X-ray powder diffraction peaks at two-theta positions 9.1° ⁇ 0.2°, 11.0° ⁇ 0.2°, 14.6° ⁇ 0.2°, 22.0° ⁇ 0.2°, 25.0° ⁇ 0.2°, 25.3° ⁇ 0.2° and 26.7° ⁇ 0.2°. (See Figure 2) (Intensity variations can occur due to processes which influence intensities most importantly the processing history of the sample)
- Form A melts with decomposition. Melting with decomposition starts at about 250°C and has an onset at about 286°C.
- Form B can be present in two states, a dry state and a wetted state. Only the characteristics of form B in the dry state are given.
- Form B is characterized by an FTIR spectrum with typical absorption bands at about 2227, 2220, 1599, 1500, 1440, 1341, 1209, 549 and 544 cm “1 .
- Form B is characterized by typical diffraction peaks at two-theta positions 4.5° ⁇ 0.2°, 8.8° ⁇ 0.2°, and 12.5° ⁇ 0.2°.
- Form B is further characterized by X-ray powder diffraction peaks at two-theta positions 10.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.2° ⁇ 0.2°, and 26.1° ⁇ 0.2°. (See Figure 4). (Intensity variations can occur due to processes which influence intensities most importantly the processing history of the sample.)
- Form C is characterized by an FTIR spectrum with typical absorption bands at about 2221, 1654, 1502, 1239, 1193 and 546 cm “1 .
- Form C is characterized by typical diffraction peaks at two-theta positions 11.9° ⁇ 0.2°, 14.3° ⁇ 0.2° and 22.3° ⁇ 0.2°.
- Form C is further characterized by X-ray powder diffraction peaks at two-theta positions 12.8° ⁇ 0.2°, 18.5° ⁇ 0.2°, 21.2° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 26.0° ⁇ 0.2°. (See Figure 6) (Intensity variations can occur due to processes which influence intensities most importantly the processing history of the sample.)
- Form D is characterized by an FTIR spectrum with typical absorption bands at about 2218, 1657, 1506, 1448, 1357, 1220 and 547 cm “1 .
- Form D is characterized by typical diffraction peaks at two-theta positions 6.6° ⁇ 0.2°, 11.6° ⁇ 0.2°, and 17.1° ⁇ 0.2°. Form D is further characterized by X-ray powder diffraction peaks at two-theta positions 15.0° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.5° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 29.8° ⁇ 0.2°. (See Figure 8). (Intensity variations can occur due to processes which influence intensities most importantly the processing history of the sample.)
- Table 1 lists solubility data of free base (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl- phenyl]amino]-2-pyrimidinyl]amino]benzonitrile and of the compound of formula (I-a).
- the free base as well as the HCl salt have a poor solubility in water as well as in 0.01 N HCl.
- Free base and HCl salt may be classified as BCS class 2 compounds.
- the solubility of the free base is significantly increased in PEG 400.
- compositions illustrating the present invention are :
- Tablet core Compound of formula (I-a) 27.5 mg (i.e. 25 mg base equivalent)
- Composition Ib Tablet core Compound of formula (I-a) 27.5 mg (i.e. 25 mg base equivalent) Lactose monohydrate 52.25 mg
- Hypromellose 2910 5mPa.s 1.75 mg Polysorbate 20 0.35 mg
- Composition Id Tablet core :
- Lactose monohydrate 159.5 mg Hypromellose 2910 15mPa.s 5.6 mg
- Composition 3d Tablet core
- Composition 5b Tablet core
- the above tablets were prepared by dissolving hypromellose or polyvinylpyrrolidone and polysorbate 20 in purified water (q.s.) followed by spraying said solution on fluidized powder consisting of a mixture of Form A and lactose monohydrate.
- the obtained granulate was dried, sieved and mixed with microcrystalline cellulose or silicified microcrystalline cellulose, croscarmellose sodium and optionally colloidal silicon dioxide.
- Magnesium stearate the powder mixture was compressed into tablets followed by film coating the tablets with a suspension of Coating powder Opadry ® II White in purified water.
- microcrystalline cellulose is preferably Avicel ® PHlOl, croscarmellose sodium is preferably Ac-Di-Sol ® ; silicified microcrystalline cellulose is preferably Prosolv ® HD90; polyvinylpyrrolidone is preferably PVP K29-32.
- the bioavailability of the compound of formula (I-a) after oral administration was compared with the bioavailability of the free base after intravenous administration.
- the formulation used for intravenous administration was a 75 % PEG 400/25 % sterile water solution of (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile free base administered at a dose of 1.25 mg/kg.
- formulations used for oral administration were : - a PEG 400 solution of (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile free base (group I);
- a capsule size 0; red cap-red body
- 8.36 % (w/w) of a compound of formula (I-a) 0.18 % (w/w) sodium lauryl sulfate, 0.18 % (w/w) silicon dioxide, 91.28 % (w/w) granulated lactose monohydrate (group III). (the % w/w is based on the capsule content)
- the different formulations were orally administered at a dose level of 5 mg base equivalent/kg.
- the formulations were prepared based on previously determined body weights of the animals. The exact administered dose was calculated using the body weights just before dosing and amounted on average to 5 mg base equivalent/kg per formulation.
- Plasma levels of 4- [ [4-[ [4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino] -2- pyrimidinyl]amino]benzonitrile (E) were determined using a qualified research LC-MS/MS method.
- LC-MS/MS analysis was carried out on an API-3000 MS/MS (Applied Biosystems), which was coupled to an HPLC-pump (Agilent) and autosampler (Inter science).
- the compound of formula (I-a) when administered as a solid dosage form, the compound of formula (I-a) has a significant better bioavailability than the corresponding free base 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile (E).
- the bioavailability is comparable with that of the free base administered as an oral PEG 400 solution.
- Treatment A a 25 mg/ml solution of free base (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6- dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile in 100% PEG 400.
- Treatment B a tablet according to composition 2a described hereinabove.
- each subject received three single doses, each equivalent to 100 mg of the free base (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile. Each dose was administered on day 1 of the respective treatment period.
- a 216- hour pharmacokinetic profile for (E) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethyl- phenyl]amino]-2-pyrimidinyl]amino]benzonitrile in plasma was determined for each session after oral administration of a single 100 mg dose of (E)-4-[[4-[[4-(2- cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile base or equivalent.
- subjects were admitted to the testing facility and fasted overnight for at least 10 hours, except for the intake of water which was allowed until 2 hours before drug intake.
- the trial medication was administered within 10 minutes after a standardized breakfast in the testing facility.
- subjects randomized to receive Treatment A or Treatment B under fed conditions the trial medication was administered within 10 minutes after a standardized breakfast in the testing facility.
- Treatment B in the fasted state the trial medication was taken without food, after an overnight fast of at least 10 hours.
- the standardized breakfast consisted of four slices of bread, two slices of ham or cheese, butter, jam and two cups of decaffeinated coffee or tea with milk and/or sugar. This meal was ingested within 20 minutes under the supervision of a trial nurse or staff member.
- trial medication was administered together with approximately 200 mL of water between 9 a.m. and 11 a.m. From 2 hours after dosing, intake of water was allowed for all subjects. Lunch was served 4.5 hours after dosing and dinner was served 10 hours after dosing. After dinner, subjects were allowed to resume their usual diet.
- Table 4 gathers the results of the human in vivo study. Table 4:
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA200700536A EA013686B1 (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile |
NZ553323A NZ553323A (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, also named TMC278 |
BRPI0514871-5A BRPI0514871A (en) | 2004-09-02 | 2005-09-02 | 4 - [[4 - [[4- (2-cyanoethenyl) -2,6-dimethylphenyl] amino] -2-pyrimidinyl] amino] benzonitrile hydrochloride |
KR1020077006837A KR101284361B1 (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-((4-(4-(2-cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino)benzonitrile |
AU2005279158A AU2005279158C1 (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile |
MX2007002595A MX2007002595A (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4- [[4 -(2-cyanoethenyl)-2, 6-dimethylphenyl] amino] -2-pyrimidinyl] amino] benzonitrile. |
JP2007528886A JP4912309B2 (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4- (2-Cyanoethenyl) -2,6-dimethylphenyl] amino] -2-pyrimidinyl] amino] benzonitrile |
CA2577288A CA2577288C (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile |
AP2007003934A AP2296A (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. |
IL181650A IL181650A (en) | 2004-09-02 | 2007-03-01 | Solid pharmaceutical composition comprising a pharmaceutically acceptable carrier and hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile and use thereof in the manufacture of a medicament for treating or preventing hiv infection |
NO20071745A NO340654B1 (en) | 2004-09-02 | 2007-04-02 | The hydrochloride salt of 4 - [[4 - [[4- (2-cyanoethenyl) -2,6-dimethylphenyl] amino] -2-pyrimidinyl] amino] benzonitrile |
NO2017062C NO2017062I1 (en) | 2005-02-25 | 2017-11-21 | Combination of - rilpivirine hydrochloride or a therapeutically equivalent form thereof and - tenofovir alafenamide or a pharmaceutically acceptable salt thereof, especially tenofovir alafenamide fumarate |
NO2017065C NO2017065I1 (en) | 2004-09-02 | 2017-11-21 | Combination of rilpivirine hydrochloride or therapeutic equivalent thereof and tenofovir, especially tenofovir disproxil fumarate |
NO2017064C NO2017064I1 (en) | 2005-02-25 | 2017-11-21 | Combination of rilpivirine hydrochloride or its therapeutic equivalent and emtricitabine |
NO2017066C NO2017066I1 (en) | 2005-02-25 | 2017-11-21 | Combination of rilpivirine hydrochloride or its therapeutic equivalent, tenofovir, especially tenofovir disproxil fumarate, and emtricitabine |
NO2017063C NO2017063I1 (en) | 2004-09-02 | 2017-11-21 | Combination of: - rilpivirine hydrochloride for a therapeutically equivalent form thereof, - emtricitabine and - tenofovir alafenamide or pharmaceutically acceptable salt thereof, especially tenofovir alafenamide fumarate |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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MYPI20043578 | 2004-09-02 | ||
MYPI20043578A MY169670A (en) | 2003-09-03 | 2004-09-02 | Combinations of a pyrimidine containing nnrti with rt inhibitors |
PCT/EP2004/052028 WO2005021001A1 (en) | 2003-09-03 | 2004-09-03 | Combinations of a pyrimidine containing nnrti with rt inhibitors |
EPPCT/EP2004/052028 | 2004-09-03 | ||
EP05101467.8 | 2005-02-25 | ||
EP05101467 | 2005-02-25 |
Publications (1)
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WO2006024668A1 true WO2006024668A1 (en) | 2006-03-09 |
Family
ID=34940340
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP2005/054342 WO2006024668A1 (en) | 2004-09-02 | 2005-09-02 | Hydrochloride of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile |
Country Status (5)
Country | Link |
---|---|
KR (1) | KR101284361B1 (en) |
AU (1) | AU2005279158C1 (en) |
CA (1) | CA2577288C (en) |
PL (1) | PL1632232T6 (en) |
WO (1) | WO2006024668A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2009007441A3 (en) * | 2007-07-12 | 2009-04-30 | Tibotec Pharm Ltd | Crystalline form of (e) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2 pyrimidinyl]amino]benzonitrile |
WO2012125993A1 (en) | 2011-03-17 | 2012-09-20 | Teva Pharmaceutical Industries Ltd. | Solid state forms of rilpivirine base, and rilipivirine salts |
AU2007206901B2 (en) * | 2006-01-20 | 2013-01-31 | Janssen Sciences Ireland Uc | Long term treatment of HIV- infection with TCM278 |
EP2604593A1 (en) * | 2011-12-14 | 2013-06-19 | Sandoz AG | Polymorph of Rilpivirine hydrochloride and its use as antiviral |
WO2013087794A1 (en) * | 2011-12-14 | 2013-06-20 | Sandoz Ag | Polymorph of rilpivirine hydrochloride and its use as antiviral |
US8841310B2 (en) | 2003-09-03 | 2014-09-23 | Janssen R & D Ireland | Combinations of a pyrimidine containing NNRTI with RT inhibitors |
US20140350038A1 (en) * | 2011-09-16 | 2014-11-27 | Hetero Research Foundation | Rilpivirine hydrochloride |
US8916558B2 (en) | 2007-03-14 | 2014-12-23 | Tibotec Pharmaceuticals Ltd. | Powders for reconstitution |
EP2155169B1 (en) * | 2007-06-08 | 2016-03-23 | Boehringer Ingelheim International GmbH | Extended release formulation of nevirapine |
EP2932970B1 (en) | 2010-01-27 | 2018-03-21 | VIIV Healthcare Company | Antiviral therapy |
WO2018077815A1 (en) | 2016-10-24 | 2018-05-03 | Janssen Sciences Ireland Uc | Dispersible compositions |
US10857102B2 (en) | 2010-11-19 | 2020-12-08 | Gilead Sciences, Inc. | Therapeutic compositions comprising rilpivirine HCL and tenofovir disoproxil fumarate |
Citations (3)
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WO2003016306A1 (en) * | 2001-08-13 | 2003-02-27 | Janssen Pharmaceutica N.V. | Hiv inhibiting pyrimidines derivatives |
WO2004016581A1 (en) * | 2002-08-09 | 2004-02-26 | Janssen Pharmaceutica N.V. | Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile |
WO2005021001A1 (en) * | 2003-09-03 | 2005-03-10 | Tibotec Pharmaceuticals Ltd. | Combinations of a pyrimidine containing nnrti with rt inhibitors |
-
2005
- 2005-09-02 AU AU2005279158A patent/AU2005279158C1/en active Active
- 2005-09-02 KR KR1020077006837A patent/KR101284361B1/en active IP Right Review Request
- 2005-09-02 WO PCT/EP2005/054342 patent/WO2006024668A1/en active Application Filing
- 2005-09-02 PL PL05108086T patent/PL1632232T6/en unknown
- 2005-09-02 CA CA2577288A patent/CA2577288C/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2003016306A1 (en) * | 2001-08-13 | 2003-02-27 | Janssen Pharmaceutica N.V. | Hiv inhibiting pyrimidines derivatives |
WO2004016581A1 (en) * | 2002-08-09 | 2004-02-26 | Janssen Pharmaceutica N.V. | Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile |
WO2005021001A1 (en) * | 2003-09-03 | 2005-03-10 | Tibotec Pharmaceuticals Ltd. | Combinations of a pyrimidine containing nnrti with rt inhibitors |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
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US8841310B2 (en) | 2003-09-03 | 2014-09-23 | Janssen R & D Ireland | Combinations of a pyrimidine containing NNRTI with RT inhibitors |
AU2007206901B2 (en) * | 2006-01-20 | 2013-01-31 | Janssen Sciences Ireland Uc | Long term treatment of HIV- infection with TCM278 |
US8916558B2 (en) | 2007-03-14 | 2014-12-23 | Tibotec Pharmaceuticals Ltd. | Powders for reconstitution |
EP2155169B1 (en) * | 2007-06-08 | 2016-03-23 | Boehringer Ingelheim International GmbH | Extended release formulation of nevirapine |
JP2010533148A (en) * | 2007-07-12 | 2010-10-21 | テイボテク・フアーマシユーチカルズ | (E) Crystalline form of 4-[[4-[[4- (2-cyanoethenyl) -2,6-dimethylphenyl] amino] -2-pyrimidinyl] amino] benzonitrile |
US8426434B2 (en) | 2007-07-12 | 2013-04-23 | Tibotec Pharmaceuticals Ltd. | Crystalline form of 4-[[4-[[4-(2-Cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]amino]benzonitrile |
WO2009007441A3 (en) * | 2007-07-12 | 2009-04-30 | Tibotec Pharm Ltd | Crystalline form of (e) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2 pyrimidinyl]amino]benzonitrile |
US10426780B2 (en) | 2010-01-27 | 2019-10-01 | Viiv Healthcare Company | Antiviral therapy |
EP2932970B1 (en) | 2010-01-27 | 2018-03-21 | VIIV Healthcare Company | Antiviral therapy |
US10857102B2 (en) | 2010-11-19 | 2020-12-08 | Gilead Sciences, Inc. | Therapeutic compositions comprising rilpivirine HCL and tenofovir disoproxil fumarate |
WO2012125993A1 (en) | 2011-03-17 | 2012-09-20 | Teva Pharmaceutical Industries Ltd. | Solid state forms of rilpivirine base, and rilipivirine salts |
EP2755959A4 (en) * | 2011-09-16 | 2015-08-26 | Hetero Research Foundation | Rilpivirine hydrochloride |
US9233935B2 (en) * | 2011-09-16 | 2016-01-12 | Hetero Research Foundation | Rilpivirine hydrochloride |
US20140350038A1 (en) * | 2011-09-16 | 2014-11-27 | Hetero Research Foundation | Rilpivirine hydrochloride |
WO2013087794A1 (en) * | 2011-12-14 | 2013-06-20 | Sandoz Ag | Polymorph of rilpivirine hydrochloride and its use as antiviral |
EP2604593A1 (en) * | 2011-12-14 | 2013-06-19 | Sandoz AG | Polymorph of Rilpivirine hydrochloride and its use as antiviral |
WO2018077815A1 (en) | 2016-10-24 | 2018-05-03 | Janssen Sciences Ireland Uc | Dispersible compositions |
US11065198B2 (en) | 2016-10-24 | 2021-07-20 | Janssen Sciences Ireland Unlimited Company | Dispersible compositions |
EP4248947A2 (en) | 2016-10-24 | 2023-09-27 | Janssen Sciences Ireland Unlimited Company | Dispersible compositions |
EP4248947A3 (en) * | 2016-10-24 | 2023-11-22 | Janssen Sciences Ireland Unlimited Company | Dispersible compositions |
Also Published As
Publication number | Publication date |
---|---|
KR20070074555A (en) | 2007-07-12 |
CA2577288A1 (en) | 2006-03-09 |
AU2005279158A1 (en) | 2006-03-09 |
AU2005279158C1 (en) | 2010-12-16 |
AU2005279158B2 (en) | 2010-06-17 |
PL1632232T3 (en) | 2011-10-31 |
CA2577288C (en) | 2010-11-30 |
KR101284361B1 (en) | 2013-07-15 |
PL1632232T6 (en) | 2022-06-27 |
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