WO2004019917A1 - Dispositivo de liberacion de droga que contiene oseltamivir y un antagonista h1 - Google Patents
Dispositivo de liberacion de droga que contiene oseltamivir y un antagonista h1 Download PDFInfo
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- WO2004019917A1 WO2004019917A1 PCT/CR2002/000005 CR0200005W WO2004019917A1 WO 2004019917 A1 WO2004019917 A1 WO 2004019917A1 CR 0200005 W CR0200005 W CR 0200005W WO 2004019917 A1 WO2004019917 A1 WO 2004019917A1
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- AYGJDUHQRFKLBG-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;dihydrate Chemical compound O.O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 AYGJDUHQRFKLBG-UHFFFAOYSA-M 0.000 description 1
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- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
Definitions
- the present invention concerns a solid oral dosage dosage form containing an antiviral agent and an Hl or antihistarriin antagonist. More particularly, the invention concerns an osmotic device in dual-release tablet, which provides a controlled (sustained) release of oseltamivir and a rapid (or immediate) release of an Hl antagonist.
- Antihistarrrinics such as histamine Hl receptor antagonists (referred to herein as “Hl antagonists” or “antiMstamines”), are used to treat seasonal allergic rhinitis (SAR) and can be used to treat nasal congestion, by example the blocked or blocked nostrils.
- SAR seasonal allergic rhinitis
- Clinical, biological and epidemiological studies have shown that respiratory infections before 3 years of age play a crucial role in the subsequent development of rhinitis and asthma. The reduction of its frequency and severity could affect the viral alteration of the immune and pulmonary systems.
- Oseltamivir (OS, GS4104, EN 241104, RO 64-0796, oseltamivir phosphate, a viral neuraminidase inhibitor) is used to treat viral infections; However, it is not used to treat nasal congestion.
- Oseltamivir is the ethyl ester prodrug of the carbocyclic transition state of the sialic acid analogue RO64-0802 (GS4071), a potent and selective inhibitor of influenza A and B virus neuraninidases.
- Oral oseltamivir was approved for the treatment of acute influenza in the United States in 1999. It has demonstrated efficacy in the treatment and prevention of influenza. For antiviral agents to be effective, they must be used within 48 hours of onset. of the symptoms of influenza. Antiviral agents reduce the duration of fever and illness in one to two and a half days and also reduce the severity of some of the symptoms. While oseltamivir reduces the severity of some of the symptoms, it does not reduce nasal congestion or excessive production of mucus in the respiratory tract to the same extent as histamine Hl receptor antagonists. Consequently, nasal congestion or excessive production of mucus in the respiratory tract persists in patients given oseltamivir.
- the absolute bioavailability of the active metabolite of oseltamivir administered orally is reported to be around 80%.
- the active metabolite is detectable in plasma within 30 minutes and reaches maximum plasma concentrations after 3 to 4 hours with the dosage form used in that work. After the peak plasma concentration is reached, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours.
- Oseltamivir is eliminated primarily by conversion and renal excretion of the active metabolite.
- the pharmacokinetic profile of the active metabolite is reported to be linear and dose proportional, with less than 2 times accumulation during an oseltamivir dosage range of 50 to 500 mg twice daily.
- Plasma concentrations reach equilibrium status within 3 days of administration twice daily with the dosage form used in that work. With a dosage of 75 mg twice a day, the steady-state plasma concentration for the active metabolite remains above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite in the steady state is approximately 25% higher in the elderly compared to young individuals, however, no dosage adjustment is necessary. In patients with renal insufficiency the metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75 mg once a day is recommended for patients with creatinine clearance less than 30 mVmin (1.8 L / h). Pharmacokinetic parameters in influenza patients are reported to be qualitatively similar to those in healthy young adults.
- J. Gwaltney discloses a therapy called COVAM, which includes a method and compositions for the treatment of the common cold.
- the method requires the nasal administration of an antiviral composition, optionally containing an antithystamine, and the concomitant oral administration of at least one anti-inflammatory agent.
- Gwaltney does not disclose a method or composition for the effective treatment of the common cold or other viral infections where both the antiviral agent and the antihistamine agent are administered orally.
- Gwaltney does not reveal or suggest a solid oral dual-release dosage form containing oseltamivir and an Hl antagonist.
- sustained-release dual-release dosage for the concomitant or sequential administration of two or more drugs contained in a single unit of the dosage form.
- an oral dual-release dosage form that provides a controlled release of an antiviral agent and a rapid release of an antittaminic agent Hl, or a controlled or sustained release of oseltamivir and rapid or rapid release is not disclosed in the art. immediate antihistamine Hl.
- conventional sustained release dosage forms such as those described above, are effective, osmotic devices such as those described by Faour et al. (US Patent No. 6,004,582), the complete content of which is incorporated herein by reference, are particularly advantageous for releasing two different dosage forms from the same osmotic tablet device.
- Faour et al. they do not reveal an osmotic device formulation comprising a slow release of oseltamivir combined with a rapid release of an Hl antagonist.
- the authors also do not disclose an osmotic device that provides the specific formulations, plasma profiles or absorption profiles of the different combinations claimed herein.
- the present invention provides a dual drug release system comprising: a first composition comprising a therapeutically effective amount of oseltamivir (OS) and at least one pharmaceutical excipient; and a second different composition comprising a therapeutically effective amount of a histamine Hl receptor antagonist; where the first composition provides a controlled or sustained release of oseltamivir and the second composition provides a rapid or immediate überation of a Wstamine Hl receptor antagonist.
- OS oseltamivir
- the drug release system is selected from the group consisting of capsules containing immediate and sustained release granules, capsules containing sustained release granules and one or more immediate release tablets, capsules containing granules of sustained überation and dust, and extended-release tablets with film or multilayer coating; 2) at least 75% of the Hl antagonist is released within approximately 120 minutes and at least 70% of the oseltamivir is released within approximately 24 hours; 3) the first drug-containing composition comprises at least one release rate modifier; 4) the second composition comprises a histamine Hl receptor antagonist and at least one pharmaceutical excipient; 5) the first and the second composition are arranged in layers relative to each other; 6) the second composition containing drug surrounds the first composition containing drug; 7) the first drug-containing composition is included in a core and the second drug-containing composition is included in a coating of one or more coatings surrounding the core; 8)
- the drug release device is a capsule containing the first and second composition, the first composition is
- An embodiment of the invention provides an osmotic device comprising: a core comprising a therapeutically effective amount of oseltamivir and at least one osmotic or osmopolymer agent where the core provides a controlled release of oseltamivir; a semipermeable membrane that surrounds the nucleus and that has a passage through it and a drug-containing coating that comprises a therapeutically effective amount of an Hl antagonist and that surrounds the semipermeable membrane, where the outer coating provides a rapid überation of the Hl antagonist.
- the osmotic device include those where: 1) the osmotic device further comprises an inert water-soluble coating between the semipermeable membrane and the drug-containing coating; 2) the osmotic device further comprises one or more other coatings surrounding the core, where the coatings are selected from the group consisting of: an inert coating soluble or erodible in water, an immediate, rapid or delayed release coating; 3) Oseltamivir is released in a controlled or sustained manner for a period of about 20 to 24 hours after exposure to an aqueous environment; 4) the antihistamine Hl is überated for a period of about 5 to 120, or 15 to 120, or 5 to 60 minutes after exposure to an aqueous environment; 5) The osmotic device has a dissolution profile of oseltamivir and a dissolution profile of the Hl antagonist as described herein.
- the Hl antagonist is selected from the group consisting of acrivastine, astemizole, azelastine, cetirizine, ebastine, epinastine, fexofenadine, loratadine, mizolastin, norastemizol, promethazine and terfenadine.
- the external coating is applied by spraying instead of compression. Applying the spray coating instead of compression is applied it forms a thinner external coating and, consequently, a smaller osmotic device is formed.
- Another aspect of the invention provides a method of treatment or relief of the symptoms of viral infection or the common cold.
- the method comprises the of a dual überation dosage form comprising oseltamivir and an Hl antagonist, where the oseltamivir is sustained überated and the Hl antagonist is rapidly überated.
- the desired therapeutic levels for the Hl antagonist are in the range of about 2 ng to about 700 ng per ml of plasma.
- the desired therapeutic levels for oseltamivir are generally in the range of about 30 to about 200 ng per ml of plasma and for the active metabolite in the range of about 250 to about 1300 ng / ml.
- Fig. 1 shows a dissolution profile of oseltamivir überado in a controlled form of the dosage form according to example 1.
- Fig. 2 shows a dissolution profile of the fexofenadine released from the dosage form according to example 1.
- Oseltamivir phosphate (RO 64-0796, GS4104) is a prodrug of oseltamivir carboxylate (RO 64-0802, GS4071), a potent and selective inhibitor of glycoprotein neiuaminidase essential for the repucation of influenza A and B viruses .
- Oseltamivir phosphate (RO 64-0796, GS4104) is a prodrug of oseltamivir carboxylate (RO 64-0802, GS4071), a potent and selective inhibitor of glycoprotein neiuaminidase essential for the repucation of influenza A and B viruses .
- oseltamivir (Tamiflu ® ) is available from Roche Pharma TM AG (Switzerland). Alternatively, oseltamivir It can be prepared according to the methods described in US Patents No. 5,763,483 (Bischofberger et al.) and No. 5,866,601 (Lew et al.), the contents of which are incorporated herein by reference.
- Hl antittastamine antagonists are available in a large number of commercial sources.
- the invention provides for the administration of oseltamivir and Hl antagonists in their forms of free base, free acid, racemate, optically pure, of diastereomers, and / or of pharmaceutically acceptable salts.
- Hl anti-stamine antagonists suitable for the invention include, for example, the first generation of antittastamines, the second generation of antithystamines, diphenhydramine, chlorferuramine, bromfen amine, triprolidine, promethazine, hydroxyzine, pinlamine, dimenhydrinate, acrivastine, azelastine, cetirizine , epinastine, fexofenadine, loratadine, mizolastine, norastemizol and promethazine These drugs are commercially available in a considerable number of pharmaceutical industries.
- pharmaceutically acceptable salts refers to derivatives of the disclosed compounds, in which the therapeutic compound is modified, obtaining acid or base salts thereof.
- pharmaceutically acceptable salts include, but are not limited to, conventional salts of organic and inorganic acids from oseltamivir or the Hl antagonist.
- Pharmaceutically acceptable salts include conventional non-toxic salts, for example, of non-toxic organic and inorganic acids.
- such conventional non-toxic salts include that derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric acids and others known to those skilled in the art and salts prepared from organic acids.
- amino acids for example, amino acids, acetic, propionic, succinic, gücóüco, stearic, lactic, ma ⁇ co, tartaric, citric, ascorbic, pamoic, maleic, tódroximaleic, phenylacetic, glutamic, benzoic, saucytute, sulfan ⁇ üco, 2-, acetoximárico toluenesulfonic, methanesulfonic, ethane disulfonic, oxáüco, isetiónico and others known by those with knowledge in the art. Listings of suitable salts are found in textbooks such as Remington s Pharmaceutical Sciences, 18 TM Ed., (Alfonso R.
- phrases "pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of the medical code, suitable for use in contact with tissues of humans and animals, without excessive toxicity, irritation, allergic response, or any other problem or complication, commensurable with a reasonable benefit / risk ratio
- Fig. 1 shows the in vitro dissolution profile of oseltamivir for the tablets described in Example 1.
- the überation profile of the dual überation formulation of the invention will go from that of Fig. 1 according to the materials used to fabricate the core. and the semipermeable membrane that covers the core
- the überation profile can be influenced by the material used to manufacture the semipermeable membrane that covers the core, by the material used to make any of the coatings on the semipermeable membrane, by the excipients present in the nucleus or by the presence of an osmoagent in the nucleus.
- the osmotic device of the invention may have a überation profile that generally resembles a pseudo second order, second order, überation profile. pseudo third order or third order
- the osmotic device will generally provide an expected average überation profile that resembles a zero order überation profile, pseudo zero order or pnmer order
- the dissolution profile for the oseltamivir of The formulation of Example 1 is generally broken as follows
- the dissolution profile of oseltamivir can also be described as follows:
- All tablets of the formulation of the invention will provide therapeutically effective levels of oseltamivir and the Hl antagonist for at least a predetermined period of time.
- the tablets of the invention will generally provide effective amounts of oseltamivir for a period of not less than 12 hours and not more than 24 hours, or not less than 10 hours and no more than 32 hours.
- the controlled überation core will generally begin to release oseltamivir within about 0.5-2.0 hours after exposure of the osmotic device to an aqueous solution.
- Example 1 provides a dissolution profile of an Hl antagonist.
- the external coating may be an immediate dissolving coating that dissolves in the oral cavity or a rapid dissolving coating that dissolves in the oral cavity, in the stomach, in the jejunum or in the duodenum.
- the dissolution profile of the Hl antagonist is generally described as follows and is shown in fig. two.
- the quick-release coating will cover the entire Hl antagonist within 2 hours after administration and at least 10% of the Hl antagonist within approximately 10-20 minutes after administration.
- the pharmacokinetic data obtained with the formulation of Example 1, which includes oseltamivir phosphate (150 mg) and fexofenadine hydrochloride (120 mg), are summarized in the following table.
- a water-soluble coating or layer which is inert or drug-containing, will generally comprise an inert and non-toxic matenal that is at least partially, and optionally substantially completely soluble or erodible in an environment of use.
- suitable for the inert or drug-containing coating will depend on the desired überation rate of the drug released from the drug-containing coating and on the desired separation between the drug's überation of the nucleus versus the überation of the drug of the coating containing the coating drug
- a coating that dissolves rapidly will be soluble in the oral cavity and / or in the upper gastrointestinal tract, such as the stomach, duodenum, jejunum or small intestine Examples of matenales are described in US Patents No. 4 576 604 of Guittard et al and No 4673 405 of Guittard et al, and No.
- the coating that dissolves quickly will be soluble in saliva, gastic juices or acidic fluids
- Matenales which are suitable for preparing the water soluble or erodible coatings of the invention include, by way of example and without being limiting, water soluble poossacid gums such as carrageenan, fucoidan, ghatti gum, tragacanth, arabinogalactan, pectin, and xanthan, water-soluble salts of poassando gums such such as sodium alginate, sodium tragacantin, sodium ghattate gum; water soluble hydroxyalkylcellulose wherein the alkyl member is straight or branched from 1 to 7 carbons such as hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose; Synthetic water soluble cellulose-based film formers such as methyl cellulose and its hydroxyalkyl methylcellulose, cellulose derivatives such as a member selected from the group consisting of hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, and hydroxybutyl methylcellulose;
- film-forming materials that can be used for this purpose include poü (vinylpinoüdona), poüvin ⁇ üco alcohol, polyethylene oxide, a mixture of gelatin and poü (vinylpu ⁇ oüdona), gelatin, glucose, saccharides, povidone, copovidone, poü copolymer (vinylpirroüdona) -poü (virolo acetate).
- the water soluble coating may comprise other pharmaceutical excipients that alter or do not alter the way in which the water soluble coating behaves Those of ordinary skill in the art will recognize that the aforementioned materials include film-forming polymers.
- hydroxypropyl cellulose microcrystalline cellulose (MCC, Avicel TM from FMC Corp.), poly (ethylene-vinyl acetate) copolymer (60:40) (ENAC from Aldrich Chemical Co .), 2-hydroxyethinetacrylate (HEMA), MMA terpolymers of HEMAMMAMA synthesized in the presence of ⁇ , ⁇ '-bis (methacryloxyxyethyloxycarboiulamino) -azobenzene, azopolymers, time-programmed enteric coating system with Pharmaceutical Profiles Coating (Time Clock®) , Ltd., UK) and calcium pectinate can be included in the water soluble coating.
- MCC microcrystalline cellulose
- HEMA 2-hydroxyethinetacrylate
- the inert erodible or water-soluble coating that covers the semipermeable wall and blocks the passage is made of synthetic or natural material which, through selective dissolution or erosion will allow the passage to be unlocked thus allowing the osmotic überation process to begin.
- the coating that dissolves or erodes slowly or rapidly can be impermeable to a first external fluid, while it is soluble in a second external fluid. This property can help achieve a controlled and selective release of the active compound from the nucleus.
- the erodible or water-soluble coating will be insoluble in the fluid of the first environment of use, such as gastric juices, acidic fluids, or polar liquids, and soluble or erodible in the fluid of a second environment of use, such as intestinal juices, fluids at substantially neutral or basic pH, or apolar fluids.
- first environment of use such as gastric juices, acidic fluids, or polar liquids
- second environment of use such as intestinal juices, fluids at substantially neutral or basic pH, or apolar fluids.
- a wide variety of other polymeric materials are known that possess these various solubility possibilities and can be included in the coating.
- Such other polymeric materials include, by way of example and without limitation, cellulose acetate phthalate (CAP), cellulose acetate trimethalate (CAT), polyvinyl acetate phthalate (PNAP), hydroxypropyl methylcellulose phthalate (HP), copolymer of poü (methacrylate ethylacrylate) (1: 1) (MA-EA), copolymer of poü (methacrylate methylmethacrylate) (1: 1) (MA-MMA), copoimer of poü (methacrylate methylmethacrylate) (1: 2), Eudragit TM L-30-D (MA-EA 1: 1), Eudragit TM Ll 00-55 (MA-EA 1: 1), hydroxypropyl methylcellulose acetate succinate (HPMCAS), Coateric TM (PVAP), Aquateric TM (CAP) , AQOAT TM (HPMCAS) and combinations thereof.
- the water soluble or erodible coating may also comprise dissolution aid
- An optional polymeric material, to be used in the erodible or water soluble coating includes enteric materials that resist the action of gastric fluid preventing permeation through the semipermeable membrane, while one or more of the materials in the core are solubilized in the gastrointestinal tract, then allowing the überation of a drug from the nucleus at the beginning of osmotic pumping.
- enteric materials that resist the action of gastric fluid preventing permeation through the semipermeable membrane, while one or more of the materials in the core are solubilized in the gastrointestinal tract, then allowing the überation of a drug from the nucleus at the beginning of osmotic pumping.
- a material that easily adapts to this type of requirement is a poü (vinylpü oüdona) -vinyl acetate copolymer, such as the material supplied by BASF through its trademark KoUidon VA64, mixed with magnesium stearate and other similar excipients.
- the water-soluble coating may also comprise povidone, which is supplied by BASF under the brand of KoUidon K 30 and hydroxypropyl methylcellulose, which is supplied by Dow under the brand name Methocel E-15.
- povidone which is supplied by BASF under the brand of KoUidon K 30
- hydroxypropyl methylcellulose which is supplied by Dow under the brand name Methocel E-15.
- These materials can be prepared in solutions containing different polymer concentrations according to the viscosity required in the solution. For example, an aqueous solution of Kolüdon K 30 at 10% w / v has a viscosity of approximately 5.5-8.5 cps at 20 ° C, and a 2% w / v aqueous solution of Methocel TM E-15 It has a viscosity of approximately 13-18 cps at 20 ° C.
- An erodible or water soluble coating may also comprise other suitable materials that are substantially resistant to gastric juices and that promote enteric or colonic release.
- the water-soluble inert coating may comprise one or more materials that do not dissolve, disintegrate, or change their structure in the stomach during the period of time that the dosage form resides in the stomach.
- Representative materials that maintain their integrity in the stomach may comprise a member selected from the group consisting of (a) keratin, keratin sandarac-tolu, salol (phenyl salicylate), salol betanaphthyl benzoate and acetotanin, salol with balsam from Peru, salol with tol ⁇ , salol with rubber, salol with stearic acid, and salol with shellac; (b) a member selected from the group consisting of formalized protein, formalized gelatin, and formalized cross-linked gelatin and exchange resins; (c) a member selected from the group consisting of myristic acid-hydrogenated castor oil-cholesterol, stearic acid-camet tallow, stearic acid-tolu balm, and stearic acid-castor oil; (d) a member selected from the group consisting of shellac, ammonium shellac, ammonia-salol shellac,
- the semipermeable membrane of the osmotic device is formed of a material that is substantially permeable to the passage of fluid from the environment of use to the core and substantially impermeable to the passage of active agent from the core.
- Many common materials that form a semipermeable wall which are known to those of ordinary knowledge in the art of pharmaceutical sciences, are suitable for these purposes. Examples of these materials are cellulose esters, cellulose ethers and cellulose esters-ethers.
- a semipermeable membrane comprising cellulose acetate (CA) and optionally poü (ethylene glycol) (PEG), in particular PEG 400, have a good performance when used in combination with the other materials required herein.
- CA and PEG provide a semipermeable membrane that gives the osmotic device a well controlled überation profile of the active agent in the core and that retains its physical and chemical integrity in the environment of use.
- the CAPEG ratio is generally in the range of from about 50-99% by weight of CA: about 50-1% by weight of PEG, and about 95% by weight of CA: about 5% by weight of PEG. The proportion can be varied to alter the permeability and finally the release profile of the osmotic device.
- Other suitable materials may include a member selected from the group of cellulose acylates such as cellulose acetate, cellulose diacetate, cellulose triacetate and combinations thereof. Many suitable polymers include those described in Argentine Patent No.
- Representative materials include a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triaclate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di, and tricellulose alkanolates, mono, di, and tricellulose aroylates, and others known to those of ordinary skill in the art.
- polymers examples include cellulose acetate having a DS up to 1 and an acetyl content up to 21%; cellulose acetate having an acetyl content of 32 to 39.8%; cellulose diacetate having a DS of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate having a DS of 2 to 3 and an acetyl content of 35 to 44.8%; and others known to those of ordinary knowledge in the art.
- More specific cellulosic polymers include cellulose propionate having a DS of 1.8 and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having a DS of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%; a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triaclates having DS of 2.9 to 3 such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate, and cellulose trioclanoate; cellulose diacylates having DS of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioclanoate, cellulose dipentale, and others known to those of ordinary skill in the art.
- Additional semipermeable polymers include acetaldehyde dimethyl acetate, cellulose ethyl acetate, cellulose acetate phthalate for use in low pH environments, cellulose methyl carbamate acetate, cellulose dimethyl aminoacetate acetate, semipermeable polyamides, semipermeable polyurethanes, semipermeable sulfonated polystyrenes , selectively crosslinked semipermeable polymers formed by coprecipitation of a pohanion and a polycation as described in US Patents No. 3,173,876, No. 3,276,586, No. 3,541,005, No. 3,541,006, and No.
- the osmotic device of the invention comprises at least one passage (pore, hole, or opening) that communicates the exterior of the semipermeable wall with the core of the device.
- the passage can be formed according to any of the known methods to form passages in a semipermeable membrane.
- Such methods include, for example, 1) making a hole through the semipermeable membrane with a wick or laser; 2) include a soluble material within the composition that forms the semipermeable membrane so that a pore is formed when the osmotic device is in an environment of aqueous use; 3) drill a hole through the semipermeable membrane; or 4) use a tablet punch that has a spike to puncture a hole through the semipermeable sheet.
- the passage can pass through the semipermeable wall and one or more of any other film coated on the semipermeable membrane or between the semipermeable membrane and the core.
- the passage or passages can be shaped as desired.
- the passage is manufactured with a laser and is coriformed as an oval, eüpse, groove, hendija, cross or circle.
- the tablet core of the present invention will comprise oseltamivir, at least one pharmaceutically acceptable excipient and optionally one or more other materials.
- tablet formulations will comprise about 0.1-99.9% by weight of oseltamivir in the core of the uncoated tablet. Acceptable ranges may vary according to the desired therapeutic response, the size of the tablet, the amount and type of excipients used in the core of the device, the Hl antagonist used and the intended use of the osmotic device.
- the controlled überation tablet is an osmotic device
- osmotically effective solutes, osmotic agents or osmoagents are added. These osmoagents can help in the suspension or dissolution of oseltamivir in the nucleus.
- Example osmoagents include organic and inorganic compounds such as salts, bases, chelating agents, sodium chloride, lithium chloride, magnesium chloride, magnesium sulfate, sulfate lithium, potassium chloride, sodium sulphite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid, raffinose, sucrose, alpha-d-lactose monohydrate, glucose, combinations thereof and other similar or equivalent materials that are widely known in the art. Osmoagents can also be incorporated into the nucleus of the osmotic device to control the drug's überation. US Patent No. 4,077,407 to Theeuwes et al, whose description is thus incorporated by reference, describes suitable osmoagents.
- the tablets of the invention may also comprise acidifying agents, adsorbents, alkalizing agents, antioxidants, buffering agents, colorants, flavorings, sweetening agents, non-sticking agents, binders, diluents, direct compression excipients, disintegrants, debonding agents, lubricants, opaquents, polishing, complexing agents, fragrances, preservatives or preservatives and combinations thereof.
- a complexing agent is an agent that complexes metal ions.
- exemplary complexing agents include disodium EDTA, edetate, pentates and others known to those of ordinary skill in the art.
- the term "acidifying agent” means a compound used to provide an acidic medium for product stability. Such compounds include, by way of example and without being omitting agents, acetic acid, amino acids, citric acid, fumaric acid, and other alpha hydroxy acids, such as hydrochloric acid, ascorbic acid and nitric acid and others known to those of ordinary skill in the art. .
- the term "calcining agent” means a compound used to provide alkaline medium for product stability.
- Such compounds include, by way of example and without being ümitating agents, ammonia solution, ammonium carbonate, diethanolamine, ina monoethanola, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine and others known to those with ordinary knowledge in art.
- the term "adsorbent” means an agent capable of retaining other molecules on its surface by physical or chemical means (cheosorption). Such compounds include, by way of example and without limitation, powdered and activated carbon and other materials known to those of ordinary skill in the art.
- antioxidant means an agent that inhibits oxidation and is consequently used to prevent the deterioration of preparations by the oxidizing process.
- Such compounds include, by way of example and without limitation, ascorbic acid, ascorbyl paünitate, burylated hydroxyanisole, molated hydroxytoluene, hypophosphorous acid, monothioghcerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite and other materials known to those with ordinary knowledge in the art.
- buffering agent or “buffering agent” means a compound used to resist changes in pH after dilution or addition of an acid or alkali.
- Such compounds include, by way of example and without being omitting agents, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and anhydrous sodium citrate and dihydrate and other materials known to those of ordinary skill in the art.
- sweetening agent means a compound used to impart sweetness to a preparation.
- Such compounds include, by way of example and without limitation, aspartame, dextrose, gücerin, mannitol, sodium saccharin, sorbitol and sucrose and other materials known to those of ordinary skill in the art.
- non-stick means an agent that prevents the adhesion of the ingredients of the formulation to the punches and molds in a tablet making machine during production.
- Such compounds include, by way of example and without limitation, magnesium stearate, talc, calcium stearate, güceryl behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to those of ordinary skill in the art. .
- binder means a substance used to cause adhesion of the dust particles in the solid dosage formulations.
- Such compounds include, by way of example and without being ümitating, acacia, alginic acid, sodium carboxymethylcellulose, poü (vüülpü ⁇ oüdona), compressible sugar (e.g., NuTab), etücellulose, gelatin, glucose, liquid, methylcellulose, povidone and pregelatinized starch and other materials known to those with ordinary knowledge in the art.
- Other binders may also be included in the dosage forms.
- binders include tragacanth, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, poü (ethylenegol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers ( PLURONIC TM F68, PLURONIC TM F127), collagen, albumin, gelatin, cellulosic derivatives in non-aqueous solvents, combinations thereof and others known to those of ordinary skill in the art.
- cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, poü (ethylenegol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers ( PLURONIC TM F68, PLURONIC TM F127), collagen, albumin, gelatin, cellulosic derivatives in non-aqueous solvents, combinations thereof and others known to those of ordinary skill in the art.
- binders include, for example, poüpropüéngücol, polyoxyethylene-poüpropUeno copolymer, polyethene ester, polyethylene sorbitan ester, polyethylene oxide, combinations thereof and other materials known to those of ordinary skill in the art.
- preservatives or preservatives means a substance or combination of substances that reduce or eliminate bacterial growth in a pharmaceutical dosage form. Examples of conservatives include Nipagin, Nipasol, isopropyl alcohol and combinations thereof.
- the term "diluent” or “charge” means an inert substance used as a charge to create the desired volume, flow and compression properties, characteristic in the preparation of solid dosage forms.
- Such compounds include, by way of example and without being ümitating, calcium monoacid phosphate, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch and other materials known to those with knowledge Ordinary in art.
- direct compression excipient means a compound used in direct compression of tablet formulations.
- Such compounds include, by way of example and without being ümitating, calcium monoacid phosphate (eg, Ditab) and other materials known to those of ordinary skill in the art.
- sliding agent means an agent used in tablet and capsule formulations to promote the fluidity of granulation.
- Such compounds include, by way of example and without being omitting agents, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to those of ordinary skill in the art.
- lubricant means a substance used in tablet formulations to reduce friction during compression of the formulation.
- Such compounds include, by way of example and without being ümitating, calcium stearate, magnesium stearate, udineral oil, stearic acid, zinc stearate and other materials known to those of ordinary skill in the art.
- tablette or capsule opacifier means a compound used to make a tablet or capsule coating opaque. It can be used alone or in combination with a dye. Such compounds include, by way of example and without being ümitating, titanium dioxide, talc and other materials known to those of ordinary skill in the art.
- tablette polishing agent means a compound used to impart an attractive shine to the coated tablets.
- Such compounds include, by way of example and without limitation, carnauba wax, white wax and other materials known to those of ordinary skill in the art.
- disintegrant means a compound used in solid dosage forms to promote the breakdown of solid mass into small particles that are dispersed or dissolved more easily.
- Example disintegrants include, by way of example and without being ümitating, starches such as corn starch, potato starch, pregelatinized starches and modifications thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g., Avicel ), calcium carboxymethyl cellulose, cellulose poüacriün potassium, (eg, Amberüte), alginates, sodium starch gcolato, gums, such as agar, guar, carob, karaya, pectin, tragacanth; Crospovidone and other materials known to those with ordinary knowledge in the art.
- starches such as corn starch, potato starch, pregelatinized starches and modifications thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g., Avicel ), calcium carboxymethyl cellulose, cellulose poüa
- “dye” tea ⁇ uino means a compound used to impart color to pharmaceutical preparations soda (eg, tablets).
- Such compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C AmariUo No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide, red, other FD&C dyes and natural coloring agents such as grape skin extract, red beet powder, beta-carotene, bijol, Carrn ⁇ n, turmeric, paprika, and other materials known to him with ordinary knowledge in the art. The amount of coloring agent used will vary as desired.
- flavoring means a compound used to impart a pleasant taste and smell to a pharmaceutical preparation.
- Example flavoring agents include synthetic flavoring and aromatic flavoring oils and / or natural oils, plant extracts, leaves, flowers, fruits, etc. and combinations thereof. These may also include cinnamon oil, gaulteria oil, peppermint oils, clove oil, bay oil, aniseed oil, eucauptus, tomülo oil, cedar leaf oil, nutmeg oil, sage oil, oil of bitter almonds and cassia oil.
- Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, damask, etc.
- Flavors that have been found particularly useful include orange, grape, cherry and commercially available chewing gum flavors and mixtures thereof.
- the amount of flavoring may depend on a number of factors, including the desired organoleptic effect.
- the flavors will be present in any quantity as those with ordinary knowledge in the art wish.
- Particular flavors are grape and cherry flavors and citrus flavors such as orange.
- the present tablets may also employ one or more commonly known agents with surface activity or cosolvents that improve wetting or disintegration of the core or layers.
- Plasticizers may also be included in the tablets to modify the properties and characteristics of the polymers used in the coatings or cores of the tablets.
- the "plasticizer” technique includes all compounds capable of plasticizing or softening a polymer or binder used in the invention.
- the plasticizer must be able to lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder.
- Plasticizers such as low molecular weight PEG, generally amputate the average molecular weight of a polymer in which they are included, thereby decreasing their glass transition temperature or softening point. Plasticizers also reduce the viscosity of a polymer It is possible that the plasticizer imparts some particularly advantageous physical properties to the osmotic device of the invention
- the plasticizers useful in the invention can include, by way of example and without being ümitating agents, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester type plasticizers, gücol ethers, poü (prop ⁇ engücol), multi-block polymers, single-block polymers, low molecular weight poü (et ⁇ léngl ⁇ col), citrate ester type plasticizers, tnacetin, propylene glycol and gücenna
- Such plasticizers may also include etuenegonchol, 1,2-butylenghcol, 2,3-butylenghcol, manurenechcol, dietutenghcol, tnetdéngücol, tetraethylenebenchol and other compounds poü (et ⁇ léngücol), monopropylenebenchol monoisopropyl ether, propylenebencol monoe
- the dosage form of the invention may also include oils, for example, non-volatile oils, such as peanut oil, sesame oil, cotton oil, corn oil and olive oil, fatty acids, such as oleic acid, acid stearic acid and isostanic acid, and esters of fatty acids, such as ethyl oleate, isopropyl minstate, fatty acid gücéndos and acetylated fatty acid gücéridos It can also be mixed with alcohols, such as ethanol, isopropanol, hexadecyl alcohol, gücerol and propdéngücol , gücerol ketals, such as 2,2-d ⁇ met ⁇ l-l, 3-d ⁇ oxolan-4-methanol, with ethers, such as poü (et ⁇ léngücol) 450, petroleum hydrocarbons, such as mineral oil and petrolatum, water, or with mixtures of the same, with or without the addition of a pharmaceutical
- Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids.
- Suitable detergents include canonical detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and inactive alkyl acetates; ammonium detergents, for example, alkyl, aryl and olefin sulfonates; alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and copolymers of poü (oxyethylene) -b / o-7ue-poü (oxypropylene); and amphoteric detergents, for example, quaternary ammonium salts of alkyl ⁇ -alkyl aminopropionates and 2-alkylimidazoline; and mixtures thereof.
- glycerol monostearate nylon, butyrate acetate cellulose, d, l-poü (lactic acid), 1,6-hexanediamine, diethylenetriamine, starches, derivatized starches, acetylated monogücéridos, coacervatos of gelatin, copoümero poü (styrene - maleic acid), gücocera, castor fat, stearyl alcohol , gücerol palmitoestearate, poü (etüeno), poly (vinyl acetate), poü (vinyl chloride), 1,3-butüén-gücoldimetacrilato, etüénglicol-dimetacrilato and methacrylate hydrogels.
- glycerol monostearate nylon, butyrate acetate cellulose, d, l-poü (lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,
- a therapeutically effective amount is the amount of oseltamivir or Hl antagonist that is sufficient to produce the desired or required therapeutic response, or in other words, the amount that is sufficient to produce an appreciable biological response when administered to a patient.
- the tablets of the invention can assume any configuration or form known in the art of pharmaceutical sciences.
- the device of the invention can be a tablet, sphere, tablet, bath, plate, paraboloid of revolution, ellipsoid of revolution or others known to those of ordinary knowledge in the art.
- the tablets may also include marks, cuts, grooves, letters and / or numbers on the surface for decoration, identification and / or other purposes.
- the tablets of the invention can be prepared according to the methods described herein or those known in the art, more specifically according to the methods described in the description incorporated herein by reference.
- the oseltamivir and the excipients that are comprised in the core are mixed in a soda, semi-wet or gelatinous form, then moistened and sieved through a specified mesh to obtain granules.
- the granules are then dried in a dryer and compressed, for example, by punching to form uncoated cores.
- the compressed and uncoated cores are then coated with a semipermeable membrane.
- the semipermeable membrane surrounding the core should be perforated with, for example, laser equipment.
- an outer covering containing the antagonist Hl is applied to the semipermeable membrane.
- An external cover can be applied by compression, but is generally applied as a spray cover.
- the spray cover is thinner and lighter than the compression cover, and therefore an osmotic device that includes spraying the outer cover is smaller than a simüar osmotic device that contains a compression cover.
- the use of a drug-containing cover that is soluble or erodible in water and sprayed allows the loading of larger amounts of drug than the use of a drug-containing cover that is soluble or erodible in water and that It is applied by compression.
- a smaller size dosage form generally results in better patient compliance in taking the solid dosage form and is therefore advantageous.
- the tablets of the invention may be coated with a te ⁇ nination cover as is commonly performed in the art to provide the desired brightness, color, taste or other aesthetic feature.
- Suitable materials for preparing the termination cover are well known in the art and are found in descriptions of many of the references cited and incorporated herein by reference.
- the method for the improvement of a viral or eüminar infection and / or reducing the severity of congestion symptoms or mucus-related symptoms associated with the viral infection comprises the step of administering an oral dosage form comprising oseltamivir and an Hl antagonist to a patient, where oseltamivir is rapidly provided, for example, within a short period of time after administration.
- the method includes the steps of providing therapeutically effective levels of both drugs. This combined treatment method will reduce the severity of congestion-related symptoms associated with a viral infection (such as influenza or a common cold) even more than treatment with oseltamivir alone.
- the advantages of the present system over the other known oseltamivir administration systems in combination with an Hl antagonist are: a greater therapeutic benefit, greater control or improvement of the symptoms associated with viral infection, a simplified fabrication and / or a better compliance with the treatment by the patient.
- osmotic devices in tablets containing oseltamivir phosphate (150 mg) and fexofenadine hydrochloride (120 mg) was prepared by mixing 197.00 g of oseltamivir phosphate, 145.00 g of mannitol (osmoagent) and 40.00 g of povidone (binder). The mixture was moistened with a mixture of 46.00 ml of 96 ° alcohol, 2.30 g of PEG 400 (plasticizer), and 10.00 g of PEG 6000.
- This moistened mixture was granulated and dried at 40-50 ° C for 4 hours; It was then screened and mixed with 2.00 g of colloidal Siücio dioxide (desüzante). The mixture was homogenized and 3.70 g of magnesium stearate (lubricant) was added. The final mixture was compressed to tablets using 10 mm diameter punches to form uncoated cores. The average weight of the uncoated cores was 400.00 mg and the hardness was 8 to 12 kp.
- a first composition was prepared to coat the uncoated cores as follows: 32.30 g of cellulose acetate (cellulose ester) and 1.7 g of PEG 400 (plasticizer) were added to a mixture 1310.0 ml of the organic solvents acetone (710 ml) and methanol (300 ml). This polymeric mixture was sprayed on the tablets in a conventional cloth until tablets coated with a film weighing on average approximately 34.0 mg were obtained. A 0.50 mm hole was drilled in one of the faces of the tablet
- the second coating was prepared by mixing 1.95 g of copoüvidone (water soluble polymer), 1.75 g of titanium dioxide (opaque), 6.25 g of talc and 50.00 mg of Ponceau Red aluminum lacquer (dye) in isopropyl alcohol. This polymer mixture was sprayed on the tablets until tablets coated with a pellet weighing on average approximately 10 mg were obtained.
- the third coating was prepared by mixing 120.00 g of fexofenadine hydrochloride, 150.00 g of microcrystalline cellulose (disintegrant), 100.00 g of lactose monohydrate, 35.00 g of corn starch and 32.00 g of povidone ( film forming polymer). The mixture was moistened and mixed with 130.00 ml of purified water, 9.00 g of PEG 400 (plasticizer) and 30.00 g of PEG 6000. This mixture was granulated and dried at 40-50 ° C for 3 hours; It was then screened and mixed with 1.00 g of colloidal Siücio dioxide (sliding). The mixture was homogenized and 6.00 g of magnesium stearate (lubricant) were also mixed.
- the final mixture was compressed on the second coating using 14.00 mm diameter punches to form tablets that weighed an average of about 483.0 mg and had a hardness of 7 to 12 kp.
- the final coating was prepared by mixing 12.10 g of HPMC 2910 (peUcula forming polymer), 3.42 g of PEG 6000 (plasticizer) and 4.48 g of titanium dioxide
- the osmoagent, diluent, binder, plasticizer, slider, disintegrant, lubricant, cellulose ester, water soluble polymer, opaque and film forming polymer used in the present invention were selected from the respective groups of ingredients mentioned above.
- the organic solvents used here they can include, for example, ethanol, methanol, isopropanol, methylene chloride, and others normally used in pharmaceutical sciences.
- EXAMPLE 2 The following general method was used to prepare osmotic devices according to the invention.
- a batch of osmotic devices in tablets containing oseltamivir phosphate (150 mg) and loratadine (10 mg) was prepared by mixing 197.00 g of oseltamivir phosphate, 55.00 g of sodium chloride (osmoagent) and 40 .00 g of povidone (binder). The mixture was moistened with a mixture of 46.00 ml of 96 ° alcohol, 2.30 g of PEG 400 (plasticizer), and 10.00 g of PEG 6000.
- This moistened mixture was granulated and dried at 40-50 ° C for 4 hours; It was then screened and mixed with 2.00 g of colloidal Siücio dioxide (desüzante). The mixture was homogenized and 3.70 g of magnesium stearate (lubricant) was added. The final mixture was compressed to tablets using 10 mm diameter punches to form uncoated cores. The average weight of the uncoated cores was 310.00 mg and the hardness was 8 to 12 kp.
- a first composition was prepared to coat the uncoated cores as detailed below: 32.30 g of cellulose acetate (cellulose ester) and 1.7 g of PEG 400 (plasticizer) were added to a mixture 1310.0 ml of the organic solvents acetone (710 ml) and methanol (300 ml). This polymeric mixture was sprayed onto the tablets in a conventional cloth until tablets coated with a film weighing on average approximately 28.0 mg were obtained.
- the second coating was prepared by mixing 1.95 g of copoüvidone (water soluble polymer), 1.75 g of titanium dioxide (opaque), 6.25 g of talc and 50.00 mg of Ponceau Red dumine lacquer (dye) in isopropyl alcohol. This polymeric mixture was sprayed on the tablets until tablets coated with a pellet weighing an average of approximately 12 mg were obtained.
- the third coating was prepared by mixing 10.00 g of loratadine, 23.40 g of
- HPMC 2910 film-forming polymer
- PEG 6000 plasticizer
- crospovidone binder
- colloidal silicon dioxide desuzant
- the final coating was prepared by mixing 12.10 g of HPMC 2910 (peUcula forming polymer), 3.42 g of PEG 6000 (plasticizer) and 4.48 g of titanium dioxide
- the osmoagent, diluent, binder, plasticizer, slider, disintegrant, lubricant, cellulose ester, water soluble polymer, opaquent and film-forming polymer used in the present invention were selected from the respective groups of ingredients mentioned above.
- the organic solvents used here they can include, for example, ethanol, methanol, isopropanol, methylene chloride, and others normally used in pharmaceutical sciences.
- EXAMPLE 3 The following procedure was used to prepare capsules that consist essentially of sustained überation oseltamivir granules and immediate überation loratadine tablets. Capsules manufactured according to this procedure include the following ingredients in approximately indicated amounts.
- the capsules were manufactured as follows. Oseltamivir phosphate and güceryl monostearate were entirely mixed and screened by USP 12 mesh. The sieve was spheronized and screened again by USP 12. The spheronized granules were coated with an aqueous dispersion of ethylcellulose containing acetylated monoglyceride (plasticizer).
- the calcium mono acid phosphate, loratadine, PH 301 microcrystalline cellulose and sodium croscarmellose were placed in a mixer and mixed for 6 minutes. Magnesium stearate was added to the mixture and the mixture was sieved by USP 60 mesh to form a composition that was connrimidated to tablets having an approximate average weight of about 130 mg.
- Capsules of size 000 were filled with a loratadine tablet and with the desired amount of oseltamivir granules required to obtain the corresponding dose.
- Capsules manufactured according to this procedure include the following ingredients in approximately indicated amounts.
- the capsules were manufactured as follows. Oseltamivir phosphate and güceryl monostearate (Myvaplex 600 P) were entirely mixed and screened by USP mesh
- the sieve was spheronized and screened again by USP maUa 12.
- the spheronized granules were coated with an aqueous dispersion of etucellulose containing acetylated monogüceride (plasticizer).
- PH 101 microcrystalline cellulose and fexofenadine were placed in a mixer and mixed for 6 minutes.
- the mixture was granulated with a solution of gelatin in water containing the dye.
- the dough was sieved by USP 12 mesh and spheronized. The sieve was dried in trays.
- the granules containing oseltamivir were mixed with the granules containing fexofenadine in the desired ratio.
- Magnesium stearate was added to the granule mixture to form a composition with which capsules of size 000 were bonded until the required dose was obtained.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU2002351655A AU2002351655A1 (en) | 2002-08-29 | 2002-08-29 | Device for release of a drug containing oseltamivir and a h1 antagonist |
PCT/CR2002/000005 WO2004019917A1 (es) | 2002-08-29 | 2002-08-29 | Dispositivo de liberacion de droga que contiene oseltamivir y un antagonista h1 |
US10/619,720 US7208176B2 (en) | 2001-07-17 | 2003-07-15 | Drug delivery device containing neuraminidase inhibitor and an H1 antagonist |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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PCT/CR2002/000005 WO2004019917A1 (es) | 2002-08-29 | 2002-08-29 | Dispositivo de liberacion de droga que contiene oseltamivir y un antagonista h1 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US09/907,486 Continuation-In-Part US6605302B2 (en) | 2001-07-17 | 2001-07-17 | Drug delivery device containing oseltamivir and an H1 antagonist |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US10/619,720 Continuation-In-Part US7208176B2 (en) | 2001-07-17 | 2003-07-15 | Drug delivery device containing neuraminidase inhibitor and an H1 antagonist |
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WO2004019917A1 true WO2004019917A1 (es) | 2004-03-11 |
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PCT/CR2002/000005 WO2004019917A1 (es) | 2001-07-17 | 2002-08-29 | Dispositivo de liberacion de droga que contiene oseltamivir y un antagonista h1 |
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Cited By (1)
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CN104367558A (zh) * | 2013-08-15 | 2015-02-25 | 北京星昊医药股份有限公司 | 一种奥司他韦冻干口崩片及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5314697A (en) * | 1992-10-23 | 1994-05-24 | Schering Corporation | Stable extended release oral dosage composition comprising loratadine and pseudoephedrine |
US20020102305A1 (en) * | 2000-01-13 | 2002-08-01 | Joaquina Faour | Osmotic device containing pseudoephedrine and an H1antagonist |
US20030044457A1 (en) * | 2001-07-17 | 2003-03-06 | Joaquina Faour | Drug delivery device containing oseltamivir and an H1 antagonist |
-
2002
- 2002-08-29 WO PCT/CR2002/000005 patent/WO2004019917A1/es not_active Application Discontinuation
- 2002-08-29 AU AU2002351655A patent/AU2002351655A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5314697A (en) * | 1992-10-23 | 1994-05-24 | Schering Corporation | Stable extended release oral dosage composition comprising loratadine and pseudoephedrine |
US20020102305A1 (en) * | 2000-01-13 | 2002-08-01 | Joaquina Faour | Osmotic device containing pseudoephedrine and an H1antagonist |
US20030044457A1 (en) * | 2001-07-17 | 2003-03-06 | Joaquina Faour | Drug delivery device containing oseltamivir and an H1 antagonist |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104367558A (zh) * | 2013-08-15 | 2015-02-25 | 北京星昊医药股份有限公司 | 一种奥司他韦冻干口崩片及其制备方法 |
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