WO2001095887A1 - Solid, orally administered, water-dispersible pharmaceutical form for the treatment of tuberculosis, containing rifampicin, isoniazid, pirazinamide and pyridoxine hydrochloride, method for obtaining and presentation form of said pharmaceutical form - Google Patents
Solid, orally administered, water-dispersible pharmaceutical form for the treatment of tuberculosis, containing rifampicin, isoniazid, pirazinamide and pyridoxine hydrochloride, method for obtaining and presentation form of said pharmaceutical form Download PDFInfo
- Publication number
- WO2001095887A1 WO2001095887A1 PCT/ES2001/000241 ES0100241W WO0195887A1 WO 2001095887 A1 WO2001095887 A1 WO 2001095887A1 ES 0100241 W ES0100241 W ES 0100241W WO 0195887 A1 WO0195887 A1 WO 0195887A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical form
- isoniazid
- rifampicin
- pyrazinamide
- pyridoxine hydrochloride
- Prior art date
Links
- 229960001225 rifampicin Drugs 0.000 title claims abstract description 61
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 title claims abstract description 60
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229960003350 isoniazid Drugs 0.000 title claims abstract description 57
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 title claims abstract description 53
- 239000011764 pyridoxine hydrochloride Substances 0.000 title claims abstract description 53
- 229960004172 pyridoxine hydrochloride Drugs 0.000 title claims abstract description 53
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000007787 solid Substances 0.000 title claims abstract description 18
- 201000008827 tuberculosis Diseases 0.000 title claims description 12
- 239000008187 granular material Substances 0.000 claims abstract description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002156 mixing Methods 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000000725 suspension Substances 0.000 claims abstract description 7
- 229960005206 pyrazinamide Drugs 0.000 claims description 55
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
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- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
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- 108010010803 Gelatin Proteins 0.000 claims description 3
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- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- -1 soniazide Chemical compound 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000003945 anionic surfactant Substances 0.000 claims description 2
- 125000002091 cationic group Chemical group 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
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- 239000008273 gelatin Substances 0.000 claims description 2
- 239000003906 humectant Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 235000021096 natural sweeteners Nutrition 0.000 claims description 2
- AEDORKVKMIVLBW-BLDDREHASA-N 3-oxo-3-[[(2r,3s,4s,5r,6r)-3,4,5-trihydroxy-6-[[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methoxy]oxan-2-yl]methoxy]propanoic acid Chemical compound OCC1=C(O)C(C)=NC=C1CO[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(=O)CC(O)=O)O1 AEDORKVKMIVLBW-BLDDREHASA-N 0.000 claims 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims 1
- 239000008108 microcrystalline cellulose Substances 0.000 claims 1
- 229940016286 microcrystalline cellulose Drugs 0.000 claims 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract 1
- 239000011159 matrix material Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 229940049413 rifampicin and isoniazid Drugs 0.000 description 5
- 230000002365 anti-tubercular Effects 0.000 description 4
- 239000013065 commercial product Substances 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 238000005429 filling process Methods 0.000 description 4
- 238000000265 homogenisation Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000004260 weight control Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 244000235659 Rubus idaeus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229920003182 Surlyn® Polymers 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
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- 230000007613 environmental effect Effects 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000007970 homogeneous dispersion Substances 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
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- 238000005550 wet granulation Methods 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000006056 Oral Tuberculosis Diseases 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- 229920003082 Povidone K 90 Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 description 1
- 229960005164 acesulfame Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 229920001282 polysaccharide Polymers 0.000 description 1
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- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- 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
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Definitions
- the invention relates to the treatment of tuberculosis and, in particular, relates to a solid pharmaceutical form of oral administration of rifampicin, isoniazid, pi-razinamide and pyridoxine hydrochloride, -. co or active ingredients, consisting of a water dispersible granulate, which can be reconstituted in water, a process for obtaining said pharmaceutical form and a presentation form of said pharmaceutical form.
- Rifampicin (3- [[(4-methyl-l-piperazinyl) imino] methyl] rifampicin) [The Merck Index, 12th Edition (1996), Monograph No. 8382, page 1413], is an antibiotic with antibacterial, bactericidal characteristics and antituberculous.
- Isoniazid (4-pyridinecarboxylic acid hydrazide) [The Merck Index, 12th Edition (1996), Monograph No. 5203, page 885], is an antibacterial agent that has antituberculous characteristics.
- Pyrazinamide [The Merck Index, 12th Edition (1996), Monograph No. 8140, page 1367], is an antibacterial agent that has antituberculous characteristics.
- rifampicin and isoniazid in the form of hard gelatin capsules and dragees is known.
- the dosages in the market have doses of 150 mg of isoniazid and 300 mg of rifampicin.
- Hard gelatin capsules present problems related to their ingestion, complex elaboration, high production cost, restrictions on the use of products that react, dissolve or permeabilize the gelatin, and require very strict storage conditions because they are very sensitive to variations in temperature and humidity. Dragees also have drawbacks related to their difficulty of ingestion and a questionable bioavailability.
- tuberculosis based on rifampicin and isoniazid is a very long treatment, which requires the daily intake of numerous capsules or dragees, with the relatively low dosages of active ingredients mentioned previously, which sometimes leads to patient to a breach, or even abandonment, of the treatment indicated by the specialist, which reduces the effectiveness of the therapeutic treatment.
- pyrazinamide is presented in the market in the form of 250 mg tablets, an amount that is very far from the. single daily dose of 1,500 mg. This means that, apart from the aforementioned disadvantages for rifampicin and isoniazid, it is necessary to add that which involves eating at least 6 daily pyrazinamide tablets to comply with the therapeutic guideline.
- the problem faced by the invention consists in developing an alternative and complementary therapy to that of the product containing rifampicin / isoniazid and pyridoxine hydrochloride, for the treatment of tuberculosis that is more comfortable for the patient, as well as more efficient.
- the solution provided by this invention is the development of a granulate comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, in a suitable, water - dispersible ratio, 'which can be reconstituted in water, resulting in a solution or suspension of pleasant taste.
- an object of this invention constitutes a new solid pharmaceutical form of oral administration for the complementary treatment of tuberculosis consisting of a water dispersible granulate, comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride.
- a further object of this invention is a process for obtaining said pharmaceutical form.
- the form of presentation of said solid pharmaceutical form of oral administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride constitutes another additional object of this invention.
- the invention provides a solid pharmaceutical form of oral administration dispersible in water for the complementary treatment of tuberculosis, hereinafter pharmaceutical form of the invention, consisting of a water dispersible granulate, comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, and It presents the following pharmaco-technical parameters:
- Humidity less than or equal to 2% by weight, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.2.32; Y
- pH between 4.0 and 6.0, determined according to the procedure described in Ph. Eur. 3 to Ed., section 2.2.3.
- the pharmaceutical form of the invention can also present, optionally, the following secondary drug-technical parameters:
- the water dispersible granulate constituting the pharmaceutical form of the invention consists of a "mixed" granulate comprising a mixture of rifampicin granulate and isoniazid and pyrazinamide granulate, the latter optionally containing pyridoxine hydrochloride, prepared separately and mixed in the desired ratio.
- the water dispersible granulate constituting the pharmaceutical form of the invention comprises a single granules of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride mixed and processed with the appropriate excipients until a single granulate containing said active principles is obtained.
- Rifampicin is a commercial product that can be obtained by different methods [see, for example, references cited in The Merck Index, 12th Edition (1996), Monograph No. 8382, page 1413].
- the pharmaceutical form of the invention may contain between 3.0- and 16.9% by weight, relative to the total, of rifampicin. In a particular embodiment, said pharmaceutical form contains approximately 12.6% by weight, relative to the total, of rifampin.
- Isoniazid is a commercial product that can be obtained by different methods [see, for example, the references cited in The Merck Index, 12th Edition (1996), Monograph no. 5203, page 885].
- the pharmaceutical form of the invention may contain between 1.5 and 8.5% by weight, based on the total, of soniazide. In a particular embodiment, the pharmaceutical form contains approximately 6.0% by weight, based on the total, of isoniazid.
- Pyrazinamide is a commercial product that can be obtained by different methods [see, for example, references cited in The Merck Index, 12th Edition (1996), Monograph No. 8140, page 1367].
- the pharmaceutical form of the invention may contain between 7.5 and 42.2% by weight, based on the total, of pyrazinamide. In a particular embodiment, the dosage form 'contains about 30.0% by weight, relative to the total, of pyrazinamide.
- the role of pyridoxine hydrochloride in the pharmaceutical form of the invention is not antituberculous in itself, although it collaborates against peripheral neuropathy caused by soniazid.
- the pharmaceutical form of the invention may contain between 0.25 and 1.4% by weight, based on the total, of pyridoxine hydrochloride. In a particular embodiment, the pharmaceutical form contains approximately 1.0% by weight, based on the total, of pyridoxine hydrochloride.
- the pharmaceutically acceptable excipients and suitable for the pharmaceutical form of the invention are selected from the sweeteners, diluents, binders, flavorings, flavorings, colorants, humectants, surfactants, and mixtures thereof, commonly used in the preparation of such pharmaceutical forms, which are not incompatible with any of the active ingredients.
- Any natural sweetener for example, a mono-, di- or polysaccharide in solid, semi-solid or liquid form, such as, may be used in the pharmaceutical form of the invention.
- the pharmaceutical form of the invention contains approximately 1.2% by weight, based on the total, of sodium saccharin.
- the pharmaceutical form of the invention contains mannitol, which can act as a diluent, in addition to as a sweetener, and has the advantage that it can be ingested by diabetic people, which extends the population range to which it can be administer the pharmaceutical form of the invention.
- Diluents that can be used in the pharmaceutical form of the invention include mannitol, lactose, starch, icrocrystalline cellulose, with any particle size, and mixtures thereof.
- the diluent may be present in the pharmaceutical form of the invention in a variable amount, usually between 25.8 and 78.1% by weight, based on the total.
- the diluent used is mannitol, for the reasons mentioned above, in an amount of approximately 44.1%, based on the total.
- Polyvinylpyrrolidones can be used as binders in the pharmaceutical form of the invention, preferably a PVP, such as Povidone K29 / 32 [Plasdone] or Povidone K90.
- the binder may be present in the pharmaceutical form of the invention in a variable amount, usually between 1.0 and 3.0% by weight, based on the total. In a particular embodiment, the pharmaceutical form contains approximately 1.7% by weight, based on the total, of PVP.
- the pharmaceutical form of the invention may not contain binders since the pharmacotherapeutic characteristics of the excipients would be exploited.
- Flavors and flavorings are substances intended to mask or improve the smell or taste of medicines.
- a pharmaceutically acceptable flavoring or flavoring can be used which gives the pharmaceutical form of the invention the appropriate organoleptic characteristics.
- the flavorings and / or flavorings incorporated in the pharmaceutical form of the invention may be present in a variable amount, usually between 1.0 and 5.0% by weight, based on the total.
- the flavoring used is the raspberry aroma, in an amount of 2.4% by weight with respect to the total.
- dyes can be incorporated in the pharmaceutical form of the invention.
- the dyes that could be used include pharmaceutically acceptable dyes that give the pharmaceutical form of the invention a certain visual coherence with the flavoring or flavoring present in the formulation.
- a surfactant selected from non-ionic, cationic, anionic surfactants, and mixtures thereof, for example, sorbates or polysorbates with any degree of esterification can be used.
- the surfactant that incorporates the pharmaceutical form of the invention may be present in a variable amount, usually between 0.8 and 1.8% by weight, based on the total.
- the surfactant is sodium lauryl sulfate which also acts as a wetting agent and is present in the pharmaceutical form of the invention in an amount of 1.0% by weight relative to the total.
- excipients that can be used in the pharmaceutical form of the invention are commercial products and are present in said pharmaceutical form in the appropriate amounts.
- the amount of excipients present in the pharmaceutical form of the invention depends on the dosage of the my sma
- the pharmaceutical form of the invention can be obtained by conventional methods known to those skilled in the preparation of galenic preparations.
- the pharmaceutical form of the invention can be obtained by a method comprising the simple mixing of all components and their subsequent processing until the granulate is obtained.
- the pharmaceutical form of the invention can be obtained by a method comprising preparing, separately, a rifampicin granulate and an isoniazid and pyrazinamide granulate, mixing both granulates in the appropriate proportion and homogenizing the mixed granulate obtained.
- the different granules can be obtained by conventional methods of making granules, for example, by a dry or wet granulation process.
- wet granulation processes comprise the mixing, kneading, drying, granulation and homogenization stages, while the dry granulation processes comprise the mixing, compaction, chopping or fragmentation, granulation and homogenization stages.
- dry granulation processes comprise the mixing, compaction, chopping or fragmentation, granulation and homogenization stages.
- Example 1 describes the production of a pharmaceutical form of the invention by means of a wet manufacturing process and its presentation in single-dose sachets with 600 mg of rifampicin, 300 mg of isoniazid, 1,500 mg of pyrazinamide and 50 mg of pyridoxine hydrochloride.
- Example 2 the production of a pharmaceutical form of the invention is described by a manufacturing process by simple mixing of the components and its presentation in single-dose sachets with 600 mg of rifampicin, 300 mg of isoniazid, 1,500 mg of pyrazinamide and 50 mg of pyridoxine hydrochloride.
- the pharmaceutical form of the invention is dispersible in water, so it can be presented in a form suitable for reconstitution with water prior to administration to the patient.
- Mixing the pharmaceutical form of the invention with water produces a dispersion or suspension of the pharmaceutical form in the water, with a pleasant taste.
- the invention further provides a form of presentation of a medicament suitable for the treatment of tuberculosis containing rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride comprising a pharmaceutical form of the invention in a given dose, generally, in a therapeutically effective dose.
- the dosage of the active ingredients in the form of presentation provided by this invention may vary within a wide range, for example, the amount of rifampin present in the form of presentation may be between 300 and 600 mg, the amount of isoniazid present.
- the amount of pyrazinamide present in the presentation form can be comprised between 750 and 1,500 mg, and the amount of pyridoxine hydrochloride present in the presentation form can be comprised between and 50 mg
- the amount of rifampicin present in the presentation form is 600 mg
- the amount of isoniazid present in the presentation form is 300 mg
- the amount of pyrazinamide present in the presentation form is 1,500 mg
- the amount of pyridoxine hydrochloride present in the presentation form is 50 mg.
- the presentation form is a single dose envelope with 600 mg of rifampicin, 300 mg of isoniazid, 1,500 mg of pyrazinamide and 50 mg of pyridoxine hydrochloride, for which said single dose contains the pharmaceutical form of the invention in an amount sufficient for the envelope to have said amounts of active ingredients.
- the form of presentation of a medicament containing an association of rifampicin, Isoniazid, pyrazinamide and pyridoxine hydrochloride consists of a bottle or bottle containing a pharmaceutical form of the invention in an amount suitable for the preparation of a extemporaneous suspension.
- the extemporaneous suspension thus prepared can provide one or several doses of treatment.
- the form of presentation of the pharmaceutical form of the invention for example, the content of an envelope or part of the contents of a bottle or bottle, is reconstituted in water until a suspension is obtained.
- the dosage depends on the case and the recommendation of the specialist.
- the pharmaceutical form of the invention and the form of presentation thereof are especially suitable for the treatment of oral tuberculosis.
- the pharmaceutical form of the invention has numerous advantages over other pharmaceutical forms of administration of the known oral rifampicin-isoniazid association, for example, rapid release of the active ingredient, greater ease and convenience of dosing, greater ease of intake, greater efficiency. therapeutic due to the presence of pyrazinamide, protective effect against peripheral neuropathy and pleasant organoleptic characteristics.
- the pharmaceutical form of the invention can be dosed so that its presentation form provides, in a single daily application, the drugs necessary for the treatment of tuberculosis in the appropriate dose for one day of treatment, thus allowing the development of forms of presentation of a drug association that contains the necessary drugs, and in the appropriate doses, for the daily treatment of tuberculosis.
- An additional advantage of the single dose sachets with 600 mg of rifampicin, 300 mg of isoniazid and 1,500 mg of pyrazinamide is that as its dosage is double, for rifampicin and isoniazid, of the existing dosages in the market (150 mg of isoniazid and 300 mg of rifampicin) and sextuple for pyrazinamide from the dosages existing in the market (250 mg), 2 tablets or dragees could be replaced daily (in the case of rifampicin and isoniazid) and 6 tablets (in the case of pyrazinamide) by a single envelope, which has the characteristics that it can be ingested better (to be dispersible) and somehow guarantees the monitoring of the treatment by the patient preventing it from being abandoned, being a Long lasting treatment.
- a process is described for the manufacture of a 15 kg batch of a solid pharmaceutical form of administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, in the form of a water-dispersible granulate, suitable for dosing in sachets containing the following composition ( above) :
- a binder solution consisting of:
- the rpm of the mixer is raised to 120 rpm and the freshly prepared binder solution is added to the granulator-mixer very slowly.
- the shredder is started at 1,400 rpm keeping the mixer at 120 rpm until a suitable filling is obtained, approximately 6 minutes.
- the product is removed, dried in a fluidized bed at 40 ° C for approximately 15 minutes to reach a humidity of less than 0.8% and sieved through a 237 ⁇ mesh.
- the sieved P granule obtained in step 1.1 is weighed and mixed with rifampin in a ratio, by weight, granule
- rifampicin of 4318 630, that is, the amount of rifampin to be added, in kg, is the result of multiplying the amount of granule P (in kg) by 630 and dividing by 4318.
- the granules are collected on barrels with a double plastic bag and a silica gel bag between them, taking samples to determine the content of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, and humidity ( ⁇ 2% specified).
- the granulate obtained has a dark red color that, reconstituted with water, yields a homogeneous dispersion of pleasant taste. Additionally, the granulate has the following far acotechnical parameters: fluidity angle: 39.9 ° pH (reconstituted): 4.9 (approximately) Bulk density: 0.533 g / ml Actual density: 0.642 g / ml
- the barrel containing the granulate is taken to the dosing room, filling envelopes in a Marchesini MS235 envelope dispenser that It has a maximum speed of 560 envelopes / minute.
- the envelope filling process is carried out in an atmosphere of controlled temperature and humidity [temperature: less than 30 ° C and relative humidity less than 25%].
- the envelopes, of Surlyn opal-aluminum, are dosed at a rate of 5,000 g ⁇ 6.0% (4,700 g - 5,300 g).
- a range of ⁇ 6% is determined as a weight control during the filling process in order to be more restrictive than the release specification, which is 7.5%.
- the corresponding controls are carried out during the procedure [for example, room environmental controls
- a process for the manufacture of a 15 kg batch of a solid pharmaceutical form of administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride is described, in the form of a water dispersible granulate, suitable for dosing in sachets containing the following composition ( above) :
- the granules are collected on barrels with a double plastic bag and a silica gel bag between them, taking samples to determine the content of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, and humidity ( ⁇ 2% specified).
- the granulate obtained has a dark red color that, reconstituted with water, yields a homogeneous dispersion of pleasant taste. Additionally, the granulate has the following pharmaco-technical parameters:
- Fluidity angle 37.7 ° pH (reconstituted): 5.06 (approximately)
- Bulk density 0.518 g / ml
- Actual density 0.634 g / ml
- the envelopes, of Surlyn opal-aluminum, are dosed at a rate of 5,000 g ⁇ 6.0% (4,700 g - 5,300 g).
- a range of + 6% is determined as a weight control during the filling process in order to be more restrictive than the release specification, which is 7.5%.
- the corresponding controls are carried out during the procedure [for example, room environmental controls
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Abstract
The pharmaceutical form contains rifampicin, isoniazid, pirazinamide and pyridoxine hydrochloride as active substances in a water-dispersible solid, granular matrix. Once reconstituted in water, said pharmaceutical gives rise to a pleasant tasting suspension. The method for obtaining said pharmaceutical form involves the following steps: simply mixing the components or separately obtaining rifampicin granules and isoniazid and pirazinamide granules and, optionally, pyridoxine hydrochloride granules; mixing and homogenizing said granules. The pharmaceutical form is suitable for preparing a presentation form of a medicament containing rifampicin, isoniazid, pirazinamide and pyridoxine hydrochloride, for example in the form of single dose envelopes containing said pharmaceutical form in a therapeutically effective dose.
Description
FORMA FARMACÉUTICA SÓLIDA DE ADMINISTRACIÓN ORAL DISPERSABLE EN AGUA PARA EL TRATAMIENTO DE LA TUBERCULOSIS CONTENIENDO RIFAMPICINA, ISONIAZIDA, PIRAZINAMIDA Y PIRIDOXINA HIDROCLORURO, PROCEDIMIENTO PARA SU OBTENCIÓN Y FORMA DE PRESENTACIÓN DE DICHA FORMA FARMACÉUTICASOLID PHARMACEUTICAL FORM OF WATER DISPERSABLE ORAL ADMINISTRATION FOR THE TREATMENT OF TUBERCULOSIS CONTAINING RIFAMPYCIN, ISONIAZIDE, PIRAZINAMIDE AND HYDROCHLORIDE PYRIDOXINE, PROCEDURE FOR OBTAINING AND FORMACUATE PRESENTATION
CAMPO DE LA INVENCIÓNFIELD OF THE INVENTION
La invención se relaciona con el tratamiento de la tuberculosis y, en particular, se refiere a una forma farmacéutica sólida de administración oral de rifampicina, isoniazida, pi-razinamida y piridoxina hidrocloruro,-. co o principios activos, consistente en un granulado dispersable en agua, que puede ser reconstituido en agua, a un procedimiento para la obtención de dicha forma farmacéutica y a una forma de presentación de dicha forma farmacéutica.The invention relates to the treatment of tuberculosis and, in particular, relates to a solid pharmaceutical form of oral administration of rifampicin, isoniazid, pi-razinamide and pyridoxine hydrochloride, -. co or active ingredients, consisting of a water dispersible granulate, which can be reconstituted in water, a process for obtaining said pharmaceutical form and a presentation form of said pharmaceutical form.
ANTECEDENTES DE LA INVENCIÓNBACKGROUND OF THE INVENTION
La rifampicina (3- [ [ (4-metil-l-piperazinil) imino]metil] rifampicina) [The Merck Index, 12th Edition (1996), Monografía n° 8382, página 1413], es un antibiótico de características antibacterianas, bactericidas y antituberculosas.Rifampicin (3- [[(4-methyl-l-piperazinyl) imino] methyl] rifampicin) [The Merck Index, 12th Edition (1996), Monograph No. 8382, page 1413], is an antibiotic with antibacterial, bactericidal characteristics and antituberculous.
La isoniazida (hidrazida del ácido 4-piridin-carboxilico) [The Merck Index, 12th Edition (1996), Monografía n° 5203, página 885] , es un agente antibacteriano que presenta características antituberculosas.Isoniazid (4-pyridinecarboxylic acid hydrazide) [The Merck Index, 12th Edition (1996), Monograph No. 5203, page 885], is an antibacterial agent that has antituberculous characteristics.
La pirazinamida [The Merck Index, 12th Edition (1996) , Monografía n° 8140, página 1367], es un agente antibacteriano que presenta características antituberculosas.Pyrazinamide [The Merck Index, 12th Edition (1996), Monograph No. 8140, page 1367], is an antibacterial agent that has antituberculous characteristics.
Se conoce la asociación de rifampicina e isoniazida en forma de cápsulas de gelatina dura y grageas. Las dosificaciones existentes en el mercado presentan unas dosis de 150 mg de isoniazida y 300 mg de rifampicina.The association of rifampicin and isoniazid in the form of hard gelatin capsules and dragees is known. The dosages in the market have doses of 150 mg of isoniazid and 300 mg of rifampicin.
Las cápsulas de gelatina dura presentan problemas relacionados con su ingestión, elaboración compleja, elevado coste de producción, restricciones de empleo de productos que
reaccionen, disuelvan o permeabilicen a la gelatina, y requieren unas condiciones de almacenamiento muy estrictas porque son muy sensibles a variaciones en la temperatura y humedad ambiental. Las grageas también presentan inconvenientes relacionados con su dificultad de ingestión y con una biodisponibilidad cuestionada .Hard gelatin capsules present problems related to their ingestion, complex elaboration, high production cost, restrictions on the use of products that react, dissolve or permeabilize the gelatin, and require very strict storage conditions because they are very sensitive to variations in temperature and humidity. Dragees also have drawbacks related to their difficulty of ingestion and a questionable bioavailability.
Por otra parte, el tratamiento de la tuberculosis a base de rifampicina e isoniazida, es un tratamiento muy largo, que requiere la ingesta diaria de numerosas cápsulas o grageas, con las relativamente bajas dosificaciones de principios activos mencionadas previamente, que, en ocasiones conduce al paciente a un incumplimiento, o incluso al abandono, del tratamiento indicado por el especialista, lo que reduce la eficacia del tratamiento terapéutico. De igual forma, la pirazinamida se presenta en el mercado en forma de comprimidos de 250 mg, cantidad ésta muy alejada de la. dosis única diaria de 1.500 mg. Esto hace que, aparte de las desventajas ya mencionadas para rifampicina e isoniazida, haya que añadir la que supone ingerir como rαinimo 6 comprimidos diarios de pirazinamida para cumplir la pauta terapéutica.On the other hand, the treatment of tuberculosis based on rifampicin and isoniazid, is a very long treatment, which requires the daily intake of numerous capsules or dragees, with the relatively low dosages of active ingredients mentioned previously, which sometimes leads to patient to a breach, or even abandonment, of the treatment indicated by the specialist, which reduces the effectiveness of the therapeutic treatment. Similarly, pyrazinamide is presented in the market in the form of 250 mg tablets, an amount that is very far from the. single daily dose of 1,500 mg. This means that, apart from the aforementioned disadvantages for rifampicin and isoniazid, it is necessary to add that which involves eating at least 6 daily pyrazinamide tablets to comply with the therapeutic guideline.
Recientemente, la compañía solicitante ha desarrollado unas formas farmacéuticas sólidas de administración oral dispersables en agua para el tratamiento de la tuberculosis, que contienen rifampicina, isoniazida y piridoxina hidrocloruro.Recently, the applicant company has developed solid pharmaceutical forms of oral administration dispersible in water for the treatment of tuberculosis, which contain rifampicin, isoniazid and pyridoxine hydrochloride.
COMPENDIO DE LA INVENCIÓNSUMMARY OF THE INVENTION
El problema al que se enfrenta la invención consiste en desarrollar una terapia alternativa y complementaria a la del producto que contiene rifampicina/ isoniazida y piridoxina hidrocloruro, para el tratamiento de la tuberculosis que resulte más cómoda para el paciente, a la vez que más eficiente.The problem faced by the invention consists in developing an alternative and complementary therapy to that of the product containing rifampicin / isoniazid and pyridoxine hydrochloride, for the treatment of tuberculosis that is more comfortable for the patient, as well as more efficient.
La solución proporcionada por esta invención consiste en el desarrollo de un granulado que comprende rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, en una proporción adecuada, dispersable en agua,' que puede ser
reconstituido en agua, dando lugar a una disolución o suspensión de sabor agradable.The solution provided by this invention is the development of a granulate comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, in a suitable, water - dispersible ratio, 'which can be reconstituted in water, resulting in a solution or suspension of pleasant taste.
Por tanto, un objeto de esta invención lo constituye una nueva forma farmacéutica sólida de administración oral para el tratamiento complementario de la tuberculosis consistente en un granulado dispersable en agua, que comprende rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro.Therefore, an object of this invention constitutes a new solid pharmaceutical form of oral administration for the complementary treatment of tuberculosis consisting of a water dispersible granulate, comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride.
Un objeto adicional de esta invención lo constituye un procedimiento para la obtención de dicha forma farmacéutica. La forma de presentación de dicha forma farmacéutica sólida de administración oral de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro constituye otro objeto adicional de esta invención.A further object of this invention is a process for obtaining said pharmaceutical form. The form of presentation of said solid pharmaceutical form of oral administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride constitutes another additional object of this invention.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓNDETAILED DESCRIPTION OF THE INVENTION
La invención proporciona una forma farmacéutica sólida de administración oral dispersable en agua para el tratamiento complementario de la tuberculosis, en adelante forma farmacéutica de la invención, que consiste en un granulado dispersable en agua, que comprende rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, y presenta los siguientes parámetros farmacotécnicos :The invention provides a solid pharmaceutical form of oral administration dispersible in water for the complementary treatment of tuberculosis, hereinafter pharmaceutical form of the invention, consisting of a water dispersible granulate, comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, and It presents the following pharmaco-technical parameters:
Ángulo de fluidez: entre 0 y 50°, determinado según el procedimiento descrito en la Farmacopea Europea, 3 a Edición, en adelante Ph. Eur. 3a Ed. , apartado 2.9.16;I flowability angle: between 0 and 50 °, measured in accordance described in the European, 3 Pharmacopoeia edition, hereinafter Ed Ph Eur 3, paragraph 2.9.16,...
Humedad: menor o igual al 2% en peso, determinado según el procedimiento descrito en Ph. Eur. 3a Ed., apartado 2.2.32; yHumidity: less than or equal to 2% by weight, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.2.32; Y
pH: entre 4,0 y 6,0, determinado según el procedimiento descrito en Ph. Eur. 3a Ed. , apartado 2.2.3.pH: between 4.0 and 6.0, determined according to the procedure described in Ph. Eur. 3 to Ed., section 2.2.3.
La forma farmacéutica de la invención también puede
presentar, opcionalmente, los siguientes parámetros fármaco- técnicos secundarios:The pharmaceutical form of the invention can also present, optionally, the following secondary drug-technical parameters:
Densidad aparente: entre 0,45 y 0,70 g/ml, determinada según el procedimiento descrito en Ph. Eur. 3a Ed., apartado 2.9.15; y/oBulk density: between 0.45 and 0.70 g / ml, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.9.15; I
Densidad real: entre 0,55 y 0,87 g/ml, determinada según el procedimiento descrito en Ph. Eur. 3a Ed., apartado 2.9.15.Real density: between 0.55 and 0.87 g / ml, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.9.15.
En una realización particular de esta invención, el granulado dispersable en agua que constituye la forma farmacéutica de la invención consiste en un granulado "mixto" que comprende una mezcla de granulado de rifampicina y de granulado de isoniazida y pirazinamida, conteniendo éste último, opcionalmente, la piridoxina hidrocloruro, preparados por separado y mezclados en la relación deseada. En otra realización particular, el granulado dispersable en agua que constituye la forma farmacéutica de la invención comprende un único granulado de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro mezclados y procesados con los excipientes adecuados hasta obtener un único granulado que contiene dichos principios activos. La rifampicina es un producto comercial que puede obtenerse por diferentes métodos [véanse, por ejemplo, las referencias citadas en The Merck Index, 12th Edition (1996), Monografía n° 8382, página 1413] . La forma farmacéutica de la invención puede contener entre 3,0- y 16,9% en peso, respecto al total, de rifampicina. En una realización particular, dicha forma farmacéutica contiene, aproximadamente, un 12,6% en peso, respecto al total, de rifampícina.In a particular embodiment of this invention, the water dispersible granulate constituting the pharmaceutical form of the invention consists of a "mixed" granulate comprising a mixture of rifampicin granulate and isoniazid and pyrazinamide granulate, the latter optionally containing pyridoxine hydrochloride, prepared separately and mixed in the desired ratio. In another particular embodiment, the water dispersible granulate constituting the pharmaceutical form of the invention comprises a single granules of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride mixed and processed with the appropriate excipients until a single granulate containing said active principles is obtained. Rifampicin is a commercial product that can be obtained by different methods [see, for example, references cited in The Merck Index, 12th Edition (1996), Monograph No. 8382, page 1413]. The pharmaceutical form of the invention may contain between 3.0- and 16.9% by weight, relative to the total, of rifampicin. In a particular embodiment, said pharmaceutical form contains approximately 12.6% by weight, relative to the total, of rifampin.
La isoniazida es un producto comercial que puede obtenerse por diferentes métodos [véanse, por ejemplo, las referencias citadas en The Merck Index, 12th Edition (1996), Monografía n°
5203, página 885] . La forma farmacéutica de la invención puede contener entre 1,5 y 8,5% en peso, respecto al total, de ísoniazida. En una realización particular, la forma farmacéutica contiene, aproximadamente, un 6,0% en peso, respecto al total, de isoniazida.Isoniazid is a commercial product that can be obtained by different methods [see, for example, the references cited in The Merck Index, 12th Edition (1996), Monograph no. 5203, page 885]. The pharmaceutical form of the invention may contain between 1.5 and 8.5% by weight, based on the total, of soniazide. In a particular embodiment, the pharmaceutical form contains approximately 6.0% by weight, based on the total, of isoniazid.
La pirazinamida es un producto comercial que puede obtenerse por diferentes métodos [véanse, por ejemplo, las referencias citadas en The Merck Index, 12th Edition (1996) , Monografía n° 8140, página 1367] . La forma farmacéutica de la invención puede contener entre 7,5 y 42,2% en peso, respecto al total, de pirazinamida. En una realización particular, la forma farmacéutica 'contiene, aproximadamente, un 30,0% en peso, respecto al total, de pirazinamida.Pyrazinamide is a commercial product that can be obtained by different methods [see, for example, references cited in The Merck Index, 12th Edition (1996), Monograph No. 8140, page 1367]. The pharmaceutical form of the invention may contain between 7.5 and 42.2% by weight, based on the total, of pyrazinamide. In a particular embodiment, the dosage form 'contains about 30.0% by weight, relative to the total, of pyrazinamide.
La piridoxina hidrocloruro (vitamina B6 hidrocloruro) es un producto comercial que puede obtenerse por diferentes métodosPyridoxine hydrochloride (vitamin B6 hydrochloride) is a commercial product that can be obtained by different methods
[véanse, por ejemplo, las referencias citadas en The Merck[see, for example, references cited in The Merck
Index, 12th Edition (1996), Monografía n° 8166, página 1372].Index, 12th Edition (1996), Monograph No. 8166, page 1372].
La función de la piridoxina hidrocloruro en la forma farmacéutica de la invención no es antituberculosa en sí misma, aunque colabora contra la neuropatía periférica producida por la ísoniazída. La forma farmacéutica de la invención puede contener entre 0,25 y 1,4% en peso, respecto al total, de piridoxina hidrocloruro. En una realización particular, la forma farmacéutica contiene, aproximadamente, un 1,0% en peso, respecto al total, de piridoxina hidrocloruro.The role of pyridoxine hydrochloride in the pharmaceutical form of the invention is not antituberculous in itself, although it collaborates against peripheral neuropathy caused by soniazid. The pharmaceutical form of the invention may contain between 0.25 and 1.4% by weight, based on the total, of pyridoxine hydrochloride. In a particular embodiment, the pharmaceutical form contains approximately 1.0% by weight, based on the total, of pyridoxine hydrochloride.
Los excipientes farmacéuticamente aceptables y adecuados para la forma farmacéutica de la invención se seleccionan entre los edulcorantes, diluyentes, aglutinantes, aromatizantes, saborizantes, colorantes, humectantes, tensioactivos, y sus mezclas, habitualmente utilizados en la elaboración de este tipo de formas farmacéuticas, que no sean incompatibles con ninguno de los principios activos.The pharmaceutically acceptable excipients and suitable for the pharmaceutical form of the invention are selected from the sweeteners, diluents, binders, flavorings, flavorings, colorants, humectants, surfactants, and mixtures thereof, commonly used in the preparation of such pharmaceutical forms, which are not incompatible with any of the active ingredients.
En la forma farmacéutica de la invención puede utilizarse cualquier edulcorante natural, por ejemplo, un mono-, di- o polisacárido en forma sólida, semisólida o líquida, tal como,
manitol, sacarosa, dextrosa, fructosa, sorbitol, xilitol, etc., o sintético, por ejemplo, sacarina sódica, Aspartamo, Acesulfame, etc., y sus mezclas, en una cantidad variable, típicamente comprendida entre 0,6 y 1,7% en peso, respecto al toral. En una realización particular, la forma farmacéutica de la invención contiene, aproximadamente, un 1,2% en peso, respecto al total, de sacarina sódica. En una realización particular, la forma farmacéutica de la invención contiene manitol, que puede actuar como diluyente, además de como edulcorante, y presenta la ventaja de que puede ser ingerido por personas diabéticas, lo que amplía el intervalo de población al que se le puede administrar la forma farmacéutica de la invención.Any natural sweetener, for example, a mono-, di- or polysaccharide in solid, semi-solid or liquid form, such as, may be used in the pharmaceutical form of the invention. mannitol, sucrose, dextrose, fructose, sorbitol, xylitol, etc., or synthetic, for example, sodium saccharin, aspartame, acesulfame, etc., and mixtures thereof, in a variable amount, typically between 0.6 and 1.7 % by weight, relative to the toral. In a particular embodiment, the pharmaceutical form of the invention contains approximately 1.2% by weight, based on the total, of sodium saccharin. In a particular embodiment, the pharmaceutical form of the invention contains mannitol, which can act as a diluent, in addition to as a sweetener, and has the advantage that it can be ingested by diabetic people, which extends the population range to which it can be administer the pharmaceutical form of the invention.
Los diluyentes que pueden usarse en la forma farmacéutica de la invención incluyen manitol, lactosa, almidón, celulosa icrocristalina, con cualquier tamaño de partícula, y sus mezclas. El diluyente puede estar presente en la forma farmacéutica de la invención en una cantidad variable, normalmente comprendida entre 25,8 y 78,1% en peso, respecto al total. En una realización particular, el diluyente utilizado es manitol, por las razones previamente mencionadas, en una cantidad del 44,1% aproximadamente, respecto al total.Diluents that can be used in the pharmaceutical form of the invention include mannitol, lactose, starch, icrocrystalline cellulose, with any particle size, and mixtures thereof. The diluent may be present in the pharmaceutical form of the invention in a variable amount, usually between 25.8 and 78.1% by weight, based on the total. In a particular embodiment, the diluent used is mannitol, for the reasons mentioned above, in an amount of approximately 44.1%, based on the total.
Polivinilpirrolidonas (PVP) , gelatinas, almidones, etc., pueden utilizarse como aglutinantes en la forma farmacéutica de la invención, preferentemente una PVP, tal como la Povidona K29/32 [Plasdone] o la Povidona K90. El aglutinante puede estar presente en la forma farmacéutica de la invención en una cantidad variable, normalmente comprendida entre 1,0 y 3,0% en peso, respecto al total. En una realización particular, la forma farmacéutica contiene, aproximadamente, un 1,7% en peso, respecto al total, de PVP. Alternativamente, cuando la forma farmacéutica de la invención se obtiene mediante mezcla simple de los componentes, la forma farmacéutica de la invención podría no contener aglutinantes ya que se aprovecharían las características farmacotécnicas de los excipientes.
Los aromatizantes y saborizanr.es son sustancias destinadas a enmascarar o mejorar el olor o el sabor de los medicamentos. En la forma farmacéutica de la invención puede utilizarse un aromatizante o saborizante farmacéuticamente aceptable que confiere a la forma farmacéutica de la invención las características organolépticas adecuadas. Los aromatizantes y/o saborizantes que incorpore la forma farmacéutica de la invención pueden estar presentes en una cantidad variable, normalmente comprendida entre 1,0 y 5,0% en peso, respecto al total. En una realización particular, el aromatizante utilizado es el aroma de frambuesa, en una cantidad del 2,4% en peso respecto al total .Polyvinylpyrrolidones (PVP), gelatins, starches, etc., can be used as binders in the pharmaceutical form of the invention, preferably a PVP, such as Povidone K29 / 32 [Plasdone] or Povidone K90. The binder may be present in the pharmaceutical form of the invention in a variable amount, usually between 1.0 and 3.0% by weight, based on the total. In a particular embodiment, the pharmaceutical form contains approximately 1.7% by weight, based on the total, of PVP. Alternatively, when the pharmaceutical form of the invention is obtained by simple mixing of the components, the pharmaceutical form of the invention may not contain binders since the pharmacotherapeutic characteristics of the excipients would be exploited. Flavors and flavorings are substances intended to mask or improve the smell or taste of medicines. In the pharmaceutical form of the invention a pharmaceutically acceptable flavoring or flavoring can be used which gives the pharmaceutical form of the invention the appropriate organoleptic characteristics. The flavorings and / or flavorings incorporated in the pharmaceutical form of the invention may be present in a variable amount, usually between 1.0 and 5.0% by weight, based on the total. In a particular embodiment, the flavoring used is the raspberry aroma, in an amount of 2.4% by weight with respect to the total.
Aunque no es necesario la incorporación de colorantes en la forma farmacéutica de la invención (debido al color rojo proporcionado por la rifampicina) , si se desea, se pueden incorporar colorantes. En este caso, los colorantes que podrían utilizarse incluyen a los colorantes farmacéuticamente aceptables que confieren a la forma farmacéutica de la invención una cierta coherencia visual con el aromatizante o saborizante presente en la formulación.Although it is not necessary to incorporate dyes in the pharmaceutical form of the invention (due to the red color provided by rifampicin), if desired, dyes can be incorporated. In this case, the dyes that could be used include pharmaceutically acceptable dyes that give the pharmaceutical form of the invention a certain visual coherence with the flavoring or flavoring present in the formulation.
Como tensioactivo puede usarse un tensioactivo seleccionado entre los tensioactivos no iónicos, catiónicos, aniónicos, y sus mezclas, por ejemplo, los sorbatos o polisorbatos con cualquier grado de esterificación. El tensioactivo que incorpore la forma farmacéutica de la invención puede estar presente en una cantidad variable, normalmente comprendida entre 0,8 y 1,8% en peso, respecto al total. En una realización particular, el tensioactivo es el lauríl sulfato sódico que también actúa como agente humectante y está presente en la forma farmacéutica de la invención en una cantidad del 1,0% en peso respecto al total.As a surfactant, a surfactant selected from non-ionic, cationic, anionic surfactants, and mixtures thereof, for example, sorbates or polysorbates with any degree of esterification can be used. The surfactant that incorporates the pharmaceutical form of the invention may be present in a variable amount, usually between 0.8 and 1.8% by weight, based on the total. In a particular embodiment, the surfactant is sodium lauryl sulfate which also acts as a wetting agent and is present in the pharmaceutical form of the invention in an amount of 1.0% by weight relative to the total.
Los excipientes que pueden ser utilizados en la forma farmacéutica de la invención son productos comerciales y están presentes en dicha forma farmacéutica en las cantidades adecuadas. La cantidad de excipientes presente en la forma farmacéut-ica de la invención depende de la dosificación de la
mi sma .The excipients that can be used in the pharmaceutical form of the invention are commercial products and are present in said pharmaceutical form in the appropriate amounts. The amount of excipients present in the pharmaceutical form of the invention depends on the dosage of the my sma
La forma farmacéutica de la invención puede obtenerse por métodos convencionales conocidos por ios técnicos en la elaboración de preparaciones galénicas. En una realización particular, la forma farmacéutica de la invención puede obtenerse mediante un procedimiento que comprende la mezcla simple de todos los componentes y su procesamiento posterior hasta obtener el granulado. En otra realización particular, la forma farmacéutica de la invención puede obtenerse mediante un procedimiento que comprende preparar, por separado, un granulado de rifampicina y un granulado de isoniazida y pirazinamida, mezclar ambos granulados en la proporción adecuada y homogeneizar el granulado mixto obtenido. Los distintos granulados pueden obtenerse por métodos convencionales de elaboración de granulados, por ejemplo, mediante un proceso de granulación por vía seca o por vía húmeda. En general, los procesos de granulación por vía húmeda comprenden las etapas de mezcla, amasado, desecación, granulación y homogeneización, mientras que los procesos de granulación por vía seca comprenden las etapas de mezcla, compactación, troceado o fragmentación, granulación y homogeneización. Una revisión sobre los distintos procesos de granulación se recoge en el libro "Tratado de Farmacia Galénica", C. Faulí i Trillo, Luzán 5, S.A. de Ediciones, Ia edición (1993), Capítulo 25. En el Ejemplo 1 se describe la producción de una forma farmacéutica de la invención mediante un proceso de fabricación por vía húmeda y su presentación en forma de sobres monodosis con 600 mg de rifampicina, 300 mg de isoniazida, 1.500 mg de pirazinamida y 50 mg de piridoxina hidrocloruro. Asimismo, -en el Ejemplo 2 se describe la producción de una forma farmacéutica de la invención mediante un proceso de fabricación por mezcla simple de los componentes y su presentación en forma de sobres monodosis con 600 mg de rifampicina, 300 mg de isoniazida, 1.500 mg de pirazinamída y 50 mg de pirídoxina hidrocloruro. La forma farmacéutica de la invención es dispersable en
agua, por lo que puede presentarse en una forma de presentación adecuada para su reconstitución con agua previa a su administración al paciente. Al mezclar la forma farmacéutica de la invención con agua se produce una dispersión o suspensión de la forma farmacéutica en el agua, de sabor agradable.The pharmaceutical form of the invention can be obtained by conventional methods known to those skilled in the preparation of galenic preparations. In a particular embodiment, the pharmaceutical form of the invention can be obtained by a method comprising the simple mixing of all components and their subsequent processing until the granulate is obtained. In another particular embodiment, the pharmaceutical form of the invention can be obtained by a method comprising preparing, separately, a rifampicin granulate and an isoniazid and pyrazinamide granulate, mixing both granulates in the appropriate proportion and homogenizing the mixed granulate obtained. The different granules can be obtained by conventional methods of making granules, for example, by a dry or wet granulation process. In general, wet granulation processes comprise the mixing, kneading, drying, granulation and homogenization stages, while the dry granulation processes comprise the mixing, compaction, chopping or fragmentation, granulation and homogenization stages. A review of the different granulation processes is included in the book "Treaty of Pharmacy Galenica", C. Faulí i Trillo, Luzán 5, SA of Editions, I to edition (1993), Chapter 25. In Example 1 describes the production of a pharmaceutical form of the invention by means of a wet manufacturing process and its presentation in single-dose sachets with 600 mg of rifampicin, 300 mg of isoniazid, 1,500 mg of pyrazinamide and 50 mg of pyridoxine hydrochloride. Also, in Example 2 the production of a pharmaceutical form of the invention is described by a manufacturing process by simple mixing of the components and its presentation in single-dose sachets with 600 mg of rifampicin, 300 mg of isoniazid, 1,500 mg of pyrazinamide and 50 mg of pyridoxine hydrochloride. The pharmaceutical form of the invention is dispersible in water, so it can be presented in a form suitable for reconstitution with water prior to administration to the patient. Mixing the pharmaceutical form of the invention with water produces a dispersion or suspension of the pharmaceutical form in the water, with a pleasant taste.
La invención proporciona, además, una forma de presentación de un medicamento adecuado para el tratamiento de la tuberculosis que contiene rifampicina, isoniazida, pírazinamída y piridoxina hidrocloruro que comprende una forma farmacéutica de la invención en una dosis determinada, generalmente, en una dosis terapéuticamente eficaz. La dosificación de los principios activos en la forma de presentación proporcionada por esta invención puede variar dentro de un amplio intervalo, por ejemplo, la cantidad de rifampicina presente en la forma de presentación puede estar comprendida entre 300 y 600 mg, la cantidad de isoniazida presente en la forma de presentación puede estar comprendida entre 150 y 300 mgr la cantidad de pirazinamida presente en la forma de presentación puede estar comprendida entre 750 y 1.500 mg, y la cantidad de piridoxína hidrocloruro presente en la forma de presentación puede estar comprendida entre 25 y 50 mg. En una realización particular, la cantidad de rifampicina presente en la forma de presentación es de 600 mg, la cantidad de isoniazida presente en la forma de presentación es de 300 mg, la cantidad de pirazinamida presente en la forma de presentación es de 1.500 mg, y la cantidad de piridoxina hidrocloruro presente en la forma de presentación es de 50 mg . En una realización particular, la forma de presentación es un sobre monodosis con 600 mg de rifampicina, 300 mg de isoniazida, 1.500 mg de pirazinamida y 50 mg de piridoxina hidrocloruro, para lo cual, dicho sobre monodosis contiene la forma farmacéutica de la invención en una cantidad suficiente para que el sobre tenga dichas cantidades de principios activos.The invention further provides a form of presentation of a medicament suitable for the treatment of tuberculosis containing rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride comprising a pharmaceutical form of the invention in a given dose, generally, in a therapeutically effective dose. . The dosage of the active ingredients in the form of presentation provided by this invention may vary within a wide range, for example, the amount of rifampin present in the form of presentation may be between 300 and 600 mg, the amount of isoniazid present. in the presentation form it can be comprised between 150 and 300 mg r the amount of pyrazinamide present in the presentation form can be comprised between 750 and 1,500 mg, and the amount of pyridoxine hydrochloride present in the presentation form can be comprised between and 50 mg In a particular embodiment, the amount of rifampicin present in the presentation form is 600 mg, the amount of isoniazid present in the presentation form is 300 mg, the amount of pyrazinamide present in the presentation form is 1,500 mg, and the amount of pyridoxine hydrochloride present in the presentation form is 50 mg. In a particular embodiment, the presentation form is a single dose envelope with 600 mg of rifampicin, 300 mg of isoniazid, 1,500 mg of pyrazinamide and 50 mg of pyridoxine hydrochloride, for which said single dose contains the pharmaceutical form of the invention in an amount sufficient for the envelope to have said amounts of active ingredients.
En una realización particular, la forma de presentación de un medicamento que contiene una asociación de rifampicina,
isoniazida, pirazinamida y piridoxina hidrocloruro, proporcionada por esta invención, consiste en un frasco o botella que contiene una forma farmacéutica de la invención en una cantidad adecuada para la preparación de una suspensión extemporánea. La suspensión extemporánea así preparada puede proporcionar una o varias dosis de tratamiento.In a particular embodiment, the form of presentation of a medicament containing an association of rifampicin, Isoniazid, pyrazinamide and pyridoxine hydrochloride, provided by this invention, consists of a bottle or bottle containing a pharmaceutical form of the invention in an amount suitable for the preparation of a extemporaneous suspension. The extemporaneous suspension thus prepared can provide one or several doses of treatment.
Para la administración de dicha asociación de principios activos, la forma de presentación de la forma farmacéutica de la invención, por ejemplo, el contenido de un sobre o parte del contenido de un frasco o botella, se reconstituye en agua hasta obtener una suspensión. La posología depende del caso y de la recomendación del especialista.For the administration of said association of active ingredients, the form of presentation of the pharmaceutical form of the invention, for example, the content of an envelope or part of the contents of a bottle or bottle, is reconstituted in water until a suspension is obtained. The dosage depends on the case and the recommendation of the specialist.
La forma farmacéutica de la invención y la forma de presentación de la misma son especialmente adecuadas para el tratamiento de la tuberculosis por vía oral. La forma farmacéutica de la invención presenta numerosas ventajas frente a otras formas farmacéuticas de administración de la asociación rifampicina-isoniazida por vía oral conocidas, por ejemplo, rápida liberación del principio activo, mayor facilidad y comodidad de dosificación, mayor facilidad de ingesta, mayor eficiencia terapéutica debido a la presencia de la pirazinamida, efecto protector contra la neuropatía periférica y características organolépticas agradables. Además, la forma farmacéutica de la invención se puede dosificar de manera que su forma de presentación proporcione, en una única aplicación diaria, los fármacos necesarios para el tratamiento de la tuberculosis en la dosis adecuada para un día de tratamiento, permitiendo de este modo el desarrollo de formas de presentación de una asociación de fármacos que contiene los fármacos necesarios, y en las dosis apropiadas, para el tratamiento diario de la tuberculosis.The pharmaceutical form of the invention and the form of presentation thereof are especially suitable for the treatment of oral tuberculosis. The pharmaceutical form of the invention has numerous advantages over other pharmaceutical forms of administration of the known oral rifampicin-isoniazid association, for example, rapid release of the active ingredient, greater ease and convenience of dosing, greater ease of intake, greater efficiency. therapeutic due to the presence of pyrazinamide, protective effect against peripheral neuropathy and pleasant organoleptic characteristics. In addition, the pharmaceutical form of the invention can be dosed so that its presentation form provides, in a single daily application, the drugs necessary for the treatment of tuberculosis in the appropriate dose for one day of treatment, thus allowing the development of forms of presentation of a drug association that contains the necessary drugs, and in the appropriate doses, for the daily treatment of tuberculosis.
Una ventaja adicional que presentan los sobres monodosis con 600 mg de rifampicina, 300 mg de isoniazida y 1.500 mg de pirazinamida, es que como su dosificación es el doble, para la rifampicina e isoniazida, de las dosificaciones existentes en
el mercado (150 mg de isoníazida y 300 mg de rifampicina) y séxtuple para pirazinamida de las dosificaciones existentes en el mercado (250 mg) , se podrían llegar a sustituir 2 comprimidos o grageas diarios (en el caso de rifampicina e isoniazida) y 6 comprimidos (en el caso de pirazinamida) por un único sobre, lo que presenta las características de que puede ser ingerido mejor (al ser dispersable) y garantiza de alguna manera el seguimiento del tratamiento por parte del paciente evitando que se abandone, al ser un tratamiento de larga duración. Estas ventajas rinden un mejor cumplimiento terapéutico por parte del paciente de las pautas de tratamiento encomendadas por el especialista, contribuyendo de ese modo a mejorar la eficacia del tratamiento.An additional advantage of the single dose sachets with 600 mg of rifampicin, 300 mg of isoniazid and 1,500 mg of pyrazinamide, is that as its dosage is double, for rifampicin and isoniazid, of the existing dosages in the market (150 mg of isoniazid and 300 mg of rifampicin) and sextuple for pyrazinamide from the dosages existing in the market (250 mg), 2 tablets or dragees could be replaced daily (in the case of rifampicin and isoniazid) and 6 tablets (in the case of pyrazinamide) by a single envelope, which has the characteristics that it can be ingested better (to be dispersible) and somehow guarantees the monitoring of the treatment by the patient preventing it from being abandoned, being a Long lasting treatment. These advantages yield a better therapeutic compliance on the part of the patient of the treatment guidelines entrusted by the specialist, thus contributing to improve the effectiveness of the treatment.
Los siguientes ejemplos sirven para ilustrar la invención y no deben ser considerados como limitativos del alcance de la misma .The following examples serve to illustrate the invention and should not be considered as limiting the scope thereof.
EJEMPLO 1 Preparación de sobres de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruroEXAMPLE 1 Preparation of sachets of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride
Se describe una procedimiento para la fabricación de un lote de 15 kg de una forma farmacéutica sólida de administración de rifampicina, isoníazída, pírazinamida y piridoxina hidrocloruro, en forma de un granulado díspersable en agua, adecuada para su dosificación en sobres conteniendo la siguiente composición (por sobre) :A process is described for the manufacture of a 15 kg batch of a solid pharmaceutical form of administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, in the form of a water-dispersible granulate, suitable for dosing in sachets containing the following composition ( above) :
Componentes Cantidad/sobreComponents Quantity / envelope
Rifampicina 600,0 mg Isoniazida 300,0 mgRifampicin 600.0 mg Isoniazide 300.0 mg
Pirazinamida 1.500,0 mgPyrazinamide 1,500.0 mg
Piridoxina hidrocloruro 50,0 mgPyridoxine hydrochloride 50.0 mg
Povidona K29/32 84,5 mgPovidone K29 / 32 84.5 mg
Sacarina sódica 60,0 mg Aroma de frambuesa 120,0 mg
Manitol 2.203, 5 mgSodium saccharin 60.0 mg Raspberry aroma 120.0 mg Mannitol 2,203.5 mg
Lauril sulfato sódico 52,0 mgSodium Lauryl Sulfate 52.0 mg
Todos los productos utilizados son productos comerciales. El procedimiento que se describe es válido y extensible, ajusfando las cantidades, para tamaños de lotes superiores o inferiores .All products used are commercial products. The procedure described is valid and extensible, adjusting the quantities, for larger or smaller batch sizes.
1.1 Preparación del granulado de pirazinamida En una granuladora-mezcladora de capacidad adecuada se añaden los siguientes productos en el orden que se indica:1.1 Preparation of pyrazinamide granulate In a granulator-mixer of adequate capacity, the following products are added in the order indicated:
- manitol: 6,6105 kg- Mannitol: 6.6105 kg
- isoniazida: 0,9000 kg- isoniazid: 0.9000 kg
- piridoxina hidrocloruro: 0,1500 kg - aroma de frambuesa: 0,3600 kg- pyridoxine hydrochloride: 0.1500 kg - raspberry aroma: 0.3600 kg
- sacarina sódica: 0,1800 kg- sodium saccharin: 0.1800 kg
- pirazinamida: 4,500 kg- pyrazinamide: 4,500 kg
Con el fin de garantizar el perfecto mezclado de los componentes, se mezcla durante 6 minutos. Se prepara una solución aglutinante constituida por:In order to guarantee the perfect mixing of the components, it is mixed for 6 minutes. A binder solution consisting of:
- Povidona K29/32: 0,2535 kg- Povidone K29 / 32: 0.2535 kg
- agua: 0, 61575 kg- water: 0.61575 kg
- etanol 96°: 0,50625 kg .- 96 ° ethanol: 0.50625 kg.
A continuación, se suben las rpm de la mezcladora a 120 rpm y se añade la solución aglutinante recién preparada a la granuladora-mezcladora muy lentamente. Cuando se ha añadido toda la solución aglutinante, se pone en marcha el triturador a 1.400 rpm manteniendo la mezcladora a 120 rpm hasta obtener un empaste adecuado, aproximadamente 6 minutos. Transcurrido ese tiempo, el producto se retira, se seca en lecho fluido a 40°C durante aproximadamente 15 minutos hasta alcanzar una humedad menor del 0,8% y se tamiza por una malla de 237 μ .Next, the rpm of the mixer is raised to 120 rpm and the freshly prepared binder solution is added to the granulator-mixer very slowly. When all the binder solution has been added, the shredder is started at 1,400 rpm keeping the mixer at 120 rpm until a suitable filling is obtained, approximately 6 minutes. After that time, the product is removed, dried in a fluidized bed at 40 ° C for approximately 15 minutes to reach a humidity of less than 0.8% and sieved through a 237 μ mesh.
1.2 Preparación del granulado final Esta operación se realiza en habitación de temperatura y
humedad controlada [temperatura < 30°C, humedad relativa < 25%] .1.2 Preparation of the final granulate This operation is carried out in room temperature and controlled humidity [temperature <30 ° C, relative humidity <25%].
El granulo P tamizado obtenido en la etapa 1.1 se pesa y se mezcla con rifampicina en una relación, en peso, granuloThe sieved P granule obtained in step 1.1 is weighed and mixed with rifampin in a ratio, by weight, granule
P: rifampicina de 4318:630, es decir, la cantidad de rifampicina a añadir, en kg, es el resultado de multiplicar la cantidad de granulo P (en kg) por 630 y dividir entre 4318.P: rifampicin of 4318: 630, that is, the amount of rifampin to be added, in kg, is the result of multiplying the amount of granule P (in kg) by 630 and dividing by 4318.
En un mezclador se adicionan 1,890 kg de rifampicina y 0,1560 kg de lauril sulfato sódico, se mezclan durante 10 minutos y, a continuación, se añaden, aproximadamente, 1,87 kg de granulo P, y se mezcla durante 10 minutos, y, seguidamente, se añade el resto del granulo P y se vuelve a mezclar durante 10 minutos.In a mixer 1,890 kg of rifampicin and 0.1560 kg of sodium lauryl sulfate are added, mixed for 10 minutes and then approximately 1.87 kg of granule P are added, and mixed for 10 minutes, and Then, the rest of the granule P is added and mixed again for 10 minutes.
Una vez finalizado el proceso de homogeneización, se recoge el granulado sobre unos barriles con doble bolsa de plástico y bolsa de gel de sílice entre ambos, tomándose muestras para determinar el contenido de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, y la humedad (< 2% especificado) .Once the homogenization process is finished, the granules are collected on barrels with a double plastic bag and a silica gel bag between them, taking samples to determine the content of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, and humidity (< 2% specified).
El granulado obtenido tiene un color rojo oscuro que, reconstituido con agua, rinde una dispersión homogénea de sabor agradable. Adicionalmente, el granulado presenta los siguientes parámetros far acotécnicos : ngulo de fluidez: 39,9° pH (reconstituido): 4,9 (aproximadamente) Densidad aparente: 0,533 g/ml Densidad real: 0,642 g/mlThe granulate obtained has a dark red color that, reconstituted with water, yields a homogeneous dispersion of pleasant taste. Additionally, the granulate has the following far acotechnical parameters: fluidity angle: 39.9 ° pH (reconstituted): 4.9 (approximately) Bulk density: 0.533 g / ml Actual density: 0.642 g / ml
1.3 Llenado-Dosificación1.3 Filling-Dosing
Una vez obtenida la aprobación de control de calidad en cuanto al contenido de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, el barril que contiene el granulado se lleva a la sala de dosificación, procediéndose al llenado de sobres en una dosificadora de sobres Marchesini MS235 que tiene una velocidad máxima de 560 sobres/minuto. El proceso de llenado de sobres se realiza en atmósfera de temperatura y humedad controladas [temperatura: inferior a 30°C y humedad relativa
inferior al 25%] .Once the quality control approval has been obtained regarding the content of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, the barrel containing the granulate is taken to the dosing room, filling envelopes in a Marchesini MS235 envelope dispenser that It has a maximum speed of 560 envelopes / minute. The envelope filling process is carried out in an atmosphere of controlled temperature and humidity [temperature: less than 30 ° C and relative humidity less than 25%].
Los sobres, de opalina-aluminio Surlyn, son dosificados a razón de 5,000 g ± 6,0% (4,700 g - 5,300 g) . Se determina como control de peso durante el proceso de llenado un intervalo de ± 6% con el fin de ser más restrictivos que la especificación de liberación, que es del 7,5%.The envelopes, of Surlyn opal-aluminum, are dosed at a rate of 5,000 g ± 6.0% (4,700 g - 5,300 g). A range of ± 6% is determined as a weight control during the filling process in order to be more restrictive than the release specification, which is 7.5%.
Durante el procedimiento se llevan a cabo los controles correspondientes [por ejemplo, controles ambientales de la salaThe corresponding controls are carried out during the procedure [for example, room environmental controls
(temperatura, humedad) , controles de peso y controles de hermeticidad de sobre] . Una vez terminado el lote se rotula adecuadamente .(temperature, humidity), weight controls and envelope tightness controls]. Once the batch is finished, it is properly labeled.
EJEMPLO 2 Preparación de sobres de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruroEXAMPLE 2 Preparation of sachets of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride
Se describe una procedimiento para la fabricación de un lote de 15 kg de una forma farmacéutica sólida de administración de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, en forma de un granulado dispersable en agua, adecuada para su dosificación en sobres conteniendo la siguiente composición (por sobre) :A process for the manufacture of a 15 kg batch of a solid pharmaceutical form of administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride is described, in the form of a water dispersible granulate, suitable for dosing in sachets containing the following composition ( above) :
Componentes Cantidad/sobreComponents Quantity / envelope
Rifampicina 600,0 mg Isoniazida 300,0 mgRifampicin 600.0 mg Isoniazide 300.0 mg
Pirazinamida 1.500,0 mgPyrazinamide 1,500.0 mg
Piridoxina hidrocloruro 50,0 gPyridoxine hydrochloride 50.0 g
Povidona K29/32 84,5 mgPovidone K29 / 32 84.5 mg
Sacarina sódica 60,0 mg Aroma de frambuesa 120,0 mgSodium saccharin 60.0 mg Raspberry aroma 120.0 mg
Manitol 2.203,5 mgMannitol 2,203.5 mg
Lauril sulfato sódico 52,0 mgSodium Lauryl Sulfate 52.0 mg
Todos los productos utilizados son productos comerciales. El procedimiento que se describe es válido y extensible,
ajustando las cantidades, para tamaños de lotes superiores o inferiores. El proceso de mezcla deberá realizarse en atmósfera de temperatura y humedad controlada.All products used are commercial products. The procedure described is valid and extensible, adjusting quantities, for larger or smaller batch sizes. The mixing process must be carried out in a controlled temperature and humidity atmosphere.
En un mezclador de capacidad adecuada se añaden los siguientes productos en el orden que se indica:In a mixer of suitable capacity, the following products are added in the order indicated:
- manitol: 3,30525 kg- Mannitol: 3,30525 kg
- rifampicina: 1,890 kg- rifampicin: 1,890 kg
- lauril sulfato sódico: 0,1560 kg- sodium lauryl sulfate: 0.1560 kg
- piridoxina hidrocloruro: 0,1500 kg - manitol: 3,30525 kg- pyridoxine hydrochloride: 0.1500 kg - mannitol: 3.30525 kg
Con el fin de garantizar el perfecto mezclado de los componentes, se mezcla durante 10 minutos.In order to guarantee the perfect mixing of the components, it is mixed for 10 minutes.
Una vez finalizado el proceso de mezcla, se añaden, en el orden que se específica, los productos que se indican a continuación:Once the mixing process is finished, the products listed below are added in the order specified:
- isoniazida: 0,900 kg (prevamente tamizada por 350 μm)- isoniazid: 0.900 kg (usually screened by 350 μm)
- pirazinamida: 4,5 kg- pyrazinamide: 4.5 kg
- aroma de frambuesa: 0,360 kg- raspberry aroma: 0.360 kg
- sacarina sódica: 0,180 kg - Povidona K29/32: 0,2535 kg- sodium saccharin: 0,180 kg - Povidone K29 / 32: 0,2535 kg
y se mezcla durante 10 minutos.and mix for 10 minutes.
Una vez finalizado el proceso de homogeneización, se recoge el granulado sobre unos barriles con doble bolsa de plástico y bolsa de gel de sílice entre ambos, tomándose muestras para determinar el contenido de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, y la humedad (< 2% especificado) .Once the homogenization process is finished, the granules are collected on barrels with a double plastic bag and a silica gel bag between them, taking samples to determine the content of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, and humidity (< 2% specified).
El granulado obtenido tiene un color rojo oscuro que, reconstituido con agua, rinde una dispersión homogénea de sabor agradable. Adicionalmente, el granulado presenta los siguientes parámetros farmacotécnicos:The granulate obtained has a dark red color that, reconstituted with water, yields a homogeneous dispersion of pleasant taste. Additionally, the granulate has the following pharmaco-technical parameters:
Ángulo de fluidez: 37,7° pH (reconstituido): 5,06 (aproximadamente) Densidad aparente: 0,518 g/ml Densidad real: 0,634 g/ml
Una ve z obtenida la aprobación de control de calidad en cuanto al contenido de rifampicina, isoniazida, pirazinamida y piridoxina hidrocioruro, el barril que contiene el granulado se lleva a la sala de dosificación, procediéndose al llenado de sobres en una dosificadora de sobres Marchesini MS235 que tiene una velocidad máxima de 560 sobres/minuto. El proceso de llenado de sobres se realiza en atmósfera de temperatura y humedad controladas [temperatura: inferior a 30°C y humedad relativa inferior al 25%] . Los sobres, de opalina-aluminio Surlyn, son dosificados a razón de 5,000 g ± 6,0% (4,700 g - 5,300 g) . Se determina como control de peso durante el proceso de llenado un intervalo de + 6% con el fin de ser más restrictivos que la especificación de liberación, que es del 7,5%. Durante el procedimiento se llevan a cabo los controles correspondientes [por ejemplo, controles ambientales de la salaFluidity angle: 37.7 ° pH (reconstituted): 5.06 (approximately) Bulk density: 0.518 g / ml Actual density: 0.634 g / ml Once the quality control approval has been obtained regarding the content of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, the barrel containing the granulate is taken to the dosing room, filling envelopes in a Marchesini MS235 envelope dispenser which has a maximum speed of 560 envelopes / minute. The envelope filling process is carried out in an atmosphere of controlled temperature and humidity [temperature: below 30 ° C and relative humidity below 25%]. The envelopes, of Surlyn opal-aluminum, are dosed at a rate of 5,000 g ± 6.0% (4,700 g - 5,300 g). A range of + 6% is determined as a weight control during the filling process in order to be more restrictive than the release specification, which is 7.5%. The corresponding controls are carried out during the procedure [for example, room environmental controls
(temperatura, humedad) , controles de peso y controles de hermeticidad de sobre] . Una vez terminado el lote se rotula adecuadamente .
(temperature, humidity), weight controls and envelope tightness controls]. Once the batch is finished, it is properly labeled.
Claims
1. Una forma farmacéutica sólida de administración oral dispersable en agua para el tratamiento complementario de la tuberculosis, caracterizada porque es un granulado dispersable en agua, que comprende rífampicina, isoniazida, pirazinamida y piridoxina hidrocloruro, junto con excipientes farmacéuticamente aceptables y adecuados para dicha forma farmacéutica, y presenta los siguientes parámetros farmacotécnicos :1. A solid pharmaceutical form of oral administration dispersible in water for the complementary treatment of tuberculosis, characterized in that it is a water dispersible granulate, comprising rhinampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride, together with pharmaceutically acceptable excipients and suitable for said form pharmaceutical, and presents the following pharmaco-technical parameters:
ngulo de fluidez: entre 0 y 50°, determinado según el procedimiento descrito en la Farmacopea Europea, 3a Edición (Ph. Eur. 3a Ed. ) , apartado 2.9.16;fluidity angle: between 0 and 50 °, determined according to the procedure described in the European Pharmacopoeia, 3rd Edition (Ph. Eur. 3 to Ed.), section 2.9.16;
Humedad: menor o igual al 2% en peso, determinado según el procedimiento descrito en Ph. Eur. 3a Ed. , apartado 2.2.32; yHumidity: less than or equal to 2% by weight, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.2.32; Y
pH: entre 4,0 y 6,0, determinado según el procedimiento descrito en Ph. Eur. 3a Ed. , apartado 2.2.3.pH: between 4.0 and 6.0, determined according to the procedure described in Ph. Eur. 3 to Ed., section 2.2.3.
2. Forma farmacéutica según la reivindicación 1, caracterizada porque presenta, además, los siguientes parámetros farmacotécnicos secundarios:2. Pharmaceutical form according to claim 1, characterized in that it also has the following secondary pharmaco-technical parameters:
Densidad aparente: entre 0,45 y 0,70 g/ml, determinada según el procedimiento descrito en Ph. Eur. 3a Ed., apartado 2.9.15; y/oBulk density: between 0.45 and 0.70 g / ml, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.9.15; I
Densidad real: entre 0,55 y 0,87 g/ml, determinada según el procedimiento descrito en Ph. Eur. 3a Ed., apartado 2.9.15.Real density: between 0.55 and 0.87 g / ml, determined according to the procedure described in Ph. Eur. 3 to Ed., Section 2.9.15.
3. Forma farmacéutica según la reivindicación 1, caracterizada porque dicho granulado dispersable en agua comprende una mezcla de un granulado de rifampicina y de un granulado de isoniazida y pirazinamida.3. Pharmaceutical form according to claim 1, characterized in that said water dispersible granulate It comprises a mixture of a rifampicin granulate and an isoniazid and pyrazinamide granulate.
4. Forma farmacéutica según la reivindicación 1, caracterizada porque dicho granulado dispersable en agua está constituido por un único granulado que comprende rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro.4. Pharmaceutical form according to claim 1, characterized in that said water dispersible granulate is constituted by a single granulate comprising rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride.
5. Forma farmacéutica según la reivindicación 1, caracterizada porque contiene entre 3,0 y 16,9% en peso, respecto al total, dé rifampicina.5. Pharmaceutical form according to claim 1, characterized in that it contains between 3.0 and 16.9% by weight, based on the total, of rifampicin.
6. Forma farmacéutica según la reivindicación 5, caracterizada porque contiene 12,6% en peso, aproximadamente, respecto al total, de rifampicina.6. Pharmaceutical form according to claim 5, characterized in that it contains approximately 12.6% by weight, relative to the total, of rifampicin.
7. Forma farmacéutica según la reivindicación 1, caracterizada porque contiene entre 1,5 y 8,5% en peso, respecto al total, de isoniazida.7. Pharmaceutical form according to claim 1, characterized in that it contains between 1.5 and 8.5% by weight, based on the total, of isoniazid.
8. Forma farmacéutica según la reivindicación 7, caracterizada porque contiene 6,0% en peso, aproximadamente, respecto al total, de isoniazida.8. Pharmaceutical form according to claim 7, characterized in that it contains approximately 6.0% by weight, relative to the total, of isoniazid.
9. Forma farmacéutica según la reivindicación 1, caracterizada porque contiene entre 7,5 y 42,2% en peso, respecto al total, de pirazinamida.9. Pharmaceutical form according to claim 1, characterized in that it contains between 7.5 and 42.2% by weight, based on the total, of pyrazinamide.
10. Forma farmacéutica ..según la reivindicación 9, caracterizada porque contiene 30,0% en peso, aproximadamente, respecto al total, de pirazinamida.10. Pharmaceutical form according to claim 9, characterized in that it contains approximately 30.0% by weight, relative to the total, of pyrazinamide.
11. Forma farmacéutica según la reivindicación 1, caracterizada porque contiene entre 0,25 y 1,4% en peso, respecto al total, de piridoxina hidrocloruro. 11. Pharmaceutical form according to claim 1, characterized in that it contains between 0.25 and 1.4% by weight, based on the total, of pyridoxine hydrochloride.
12. Forma farmacéutica según la reivindicación 11, caracterizada porque contiene 1,0% en peso, aproximadamente, respecto al total, de piridoxina hidrocloruro.12. Pharmaceutical form according to claim 11, characterized in that it contains approximately 1.0% by weight, relative to the total, of pyridoxine hydrochloride.
13. Forma farmacéutica según la reivindicación 1, caracterizada porque dichos excipientes farmacéuticamente aceptables se seleccionan entre edulcorantes, diluyentes, aglutinantes, aromatizantes, saborizantes, colorantes, humectantes, tensioactivos , y sus mezclas.13. Pharmaceutical form according to claim 1, characterized in that said pharmaceutically acceptable excipients are selected from sweeteners, diluents, binders, flavorings, flavorings, colorants, humectants, surfactants, and mixtures thereof.
14. Forma farmacéutica según la reivindicación 13, caracterizada"' porque dicho edulcorante se selecciona entre un edulcorante natural, un edulcorante sintético y sus mezclas.14. A dosage form according to claim 13, characterized "" in that said sweetener is selected from a natural sweetener, a synthetic sweetener , and mixtures thereof.
15. Forma farmacéutica según la reivindicación 14, caracterizada porque dicho edulcorante se selecciona entre manitol, sacarina sódica y sus mezclas .15. Pharmaceutical form according to claim 14, characterized in that said sweetener is selected from mannitol, sodium saccharin and mixtures thereof.
16. Forma farmacéutica según la reivindicación 13, caracterizada porque dicho diluyente se selecciona entre manitol, lactosa, almidón o celulosa microcristalína.16. Pharmaceutical form according to claim 13, characterized in that said diluent is selected from mannitol, lactose, starch or microcrystalline cellulose.
17. Forma farmacéutica según la reivindicación 13, caracterizada porque dicho ' aglutinante se selecciona entre polivinilpirrolidona, gelatina o almidón.17. A dosage form according to claim 13, characterized in that said 'binder is selected from polyvinylpyrrolidone, gelatin or starch.
18. Forma farmacéutica según la reivindicación 13, caracterizada porque dicho aromatizante es aroma de frambuesa.18. Pharmaceutical form according to claim 13, characterized in that said flavoring is raspberry aroma.
19. Forma farmacéutica según la reivindicación 13, caracterizada porque dicho tensíoactivo se selecciona entre tensioactivos no iónicos, catiónicos, aniónícos, y sus mezclas.19. Pharmaceutical form according to claim 13, characterized in that said surfactant is selected from nonionic, cationic, anionic surfactants, and mixtures thereof.
20. Forma farmacéutica según la reivindicación 19, caracterizada porque dicho tensioactivo es lauril sulfato sódico .20. Pharmaceutical form according to claim 19, characterized in that said surfactant is lauryl sulfate sodium
21. Un procedimiento para la obtención de una forma farmacéutica sólida de administración oral de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según cualquiera de las reivindicaciones 1 a 20, que comprende la etapa de mezclar todos los componentes.21. A process for obtaining a solid pharmaceutical form of oral administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to any one of claims 1 to 20, which comprises the step of mixing all the components.
22. Un procedimiento para la obtención de una forma farmacéutica sólida de administración oral de rifampicina, ísoniazida, pirazinamida y piridoxina hidrocloruro según cualquiera dé las reivindicaciones 1 a 20, que comprende preparar, por separado, un granulado de rifampicina y un granulado de isoniazida y pirazinamida, que, opcionalmente comprende la piridoxina hidrocloruro, mezclar ambos granulados y homogeneizar el granulado mixto obtenido.22. A process for obtaining a solid pharmaceutical form of oral administration of rifampicin, soniazide, pyrazinamide and pyridoxine hydrochloride according to any one of claims 1 to 20, which comprises preparing, separately, a rifampicin granulate and an isoniazid granulate and Pyrazinamide, which optionally comprises pyridoxine hydrochloride, mixing both granules and homogenizing the mixed granulate obtained.
23. Una forma de presentación de un medicamento que contiene rifampicina, ispniazida, pirazinamida y piridoxina hidrocloruro, que comprende una forma farmacéutica sólida de administración oral de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según cualquiera de las reivindicaciones 1 a 20, en una cantidad terapéuticamente eficaz.23. A form of presentation of a medicament containing rifampicin, ispniazide, pyrazinamide and pyridoxine hydrochloride, comprising a solid pharmaceutical form of oral administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to any of claims 1 to 20, in an amount therapeutically effective.
24. Forma de presentación de un medicamento que contiene rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según la reivindicación 23, que contiene entre 300 y 600 mg de rifampicina, entre 150 y 300 mg de isoniazida, entre 750 y 1.500 mg de pirazinamida y entre 25 y 50 mg de piridoxina hidrocloruro.24. Form of presentation of a medicament containing rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to claim 23, containing between 300 and 600 mg of rifampin, between 150 and 300 mg of isoniazid, between 750 and 1,500 mg of pyrazinamide and between 25 and 50 mg of pyridoxine hydrochloride.
25. Forma de presentación de un medicamento que contiene rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según cualquiera de las reivindicaciones 23 ó 24, que consiste en un sobre monodosis que contiene dicha forma farmacéutica sólida de administración oral de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según cualquiera de las reivindicaciones 1 a 20.25. Form of presentation of a medicament containing rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to any of claims 23 or 24, which consists of a single dose envelope containing said pharmaceutical form. oral administration solid of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to any one of claims 1 to 20.
26. Forma de presentación de un medicamento que contiene rif arαpicina, isoniazida, pirazinamida y piridoxina hidrocloruro según la reivindicación 25, que consiste en un sobre monodosis que contiene la siguiente formulación:26. Form of presentation of a medicament containing rif arαpicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to claim 25, consisting of a single dose envelope containing the following formulation:
Componentes Cantidad/sobreComponents Quantity / envelope
Rifampicina 600,0 mgRifampicin 600.0 mg
Isoniazida " 300,0 mgIsoniazide " 300.0 mg
Pirazinamida 1.500,0 mgPyrazinamide 1,500.0 mg
Piridoxina hidrocloruro 50,0 mg Povidona 84,5 mgPyridoxine hydrochloride 50.0 mg Povidone 84.5 mg
Sacarina sódica 60,0 mgSodium saccharin 60.0 mg
Aroma de frambuesa 120,0 mgRaspberry Aroma 120.0 mg
Manitol 2.203,5 mgMannitol 2,203.5 mg
Lauril sulfato sódico 52,0 mgSodium Lauryl Sulfate 52.0 mg
27. Forma de presentación de un medicamento que contiene rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según la reivindicación 23, que consiste en un frasco c botella que contiene dicha forma farmacéutica sólida de administración oral de rifampicina, isoniazida, pirazinamida y piridoxina hidrocloruro según cualquiera de las reivindicaciones 1 a 20, para la preparación de una solución o suspensión extemporánea. 27. Form of presentation of a medicament containing rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to claim 23, which consists of a bottle with a bottle containing said solid pharmaceutical form of oral administration of rifampicin, isoniazid, pyrazinamide and pyridoxine hydrochloride according to any of claims 1 to 20, for the preparation of an extemporaneous solution or suspension.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU74116/01A AU7411601A (en) | 2000-06-13 | 2001-06-12 | Solid, orally administered, water-dispersible pharmaceutical form for the treatment of tuberculosis, containing rifampicin, isoniazid, pirazinamide and pyridoxine hydrochloride, method for obtaining and presentation form of said pharmaceutical form |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200001483A ES2184561B1 (en) | 2000-06-13 | 2000-06-13 | SOLID PHARMACEUTICAL FORM OF ORAL DISPERSABLE ADMINISTRATION IN WATER FOR THE TREATMENT OF TUBERCULOSIS CONTAINING RIFAMPYCIN, ISONIAZIDE, PYRAZINAMIDE AND HYDROCHLORINE PYRIDOXINE, PROCEDURE FOR OBTAINING AND FORM OF PRESENTATION FORCES. |
| ESP200001483 | 2000-06-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2001095887A1 true WO2001095887A1 (en) | 2001-12-20 |
Family
ID=8493880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/ES2001/000241 WO2001095887A1 (en) | 2000-06-13 | 2001-06-12 | Solid, orally administered, water-dispersible pharmaceutical form for the treatment of tuberculosis, containing rifampicin, isoniazid, pirazinamide and pyridoxine hydrochloride, method for obtaining and presentation form of said pharmaceutical form |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7411601A (en) |
| ES (1) | ES2184561B1 (en) |
| WO (1) | WO2001095887A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101785771A (en) * | 2010-03-05 | 2010-07-28 | 张徐红 | Compound isoniazid tablet |
| WO2011034462A1 (en) * | 2009-09-16 | 2011-03-24 | Открытое Акционерное Общество "Xиmиko-Фapmaцebtичeckий Комбинат "Akpиxиh" | Combined anti-tuberculosis preparation |
| FR2963236A1 (en) * | 2010-07-28 | 2012-02-03 | Pharma 5 Lab | Preparing composition containing e.g. rifampicin, and optionally ethambutol, comprises wet granulation of isoniazid, pyrazinamide and optionally ethambutol by wetting with binder in solvent, drying and adding rifampicin |
| WO2012013756A3 (en) * | 2010-07-28 | 2012-03-29 | Laboratoires Pharma 5 | Method for preparing tablets combining rifampicin, isoniazid, pyrazinamide and, optionally, ethambutol |
| CN103816545A (en) * | 2013-10-30 | 2014-05-28 | 安徽万邦医药科技有限公司 | Pharmaceutical composition containing rifampicin and sodium dodecyl sulfate |
| WO2015107375A1 (en) | 2013-12-20 | 2015-07-23 | Vergara Campillo Ramiro Moises | Combination of pyridoxine, folic acid and magnesium ions for treating cancer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3784553A (en) * | 1972-01-17 | 1974-01-08 | Made Labor Sa | Pyridoxine alpha-ketoglutarate and its derivatives |
| BE1010972A6 (en) * | 1996-10-09 | 1999-03-02 | Lupin Lab Ltd | Pharmaceutical anti-tuberculosis composition and method intended to produce said composition |
| RO114406B1 (en) * | 1997-12-12 | 1999-04-30 | Univ De Vest Vasile Goldis | Drug for treating tuberculosis and process for preparing the same |
-
2000
- 2000-06-13 ES ES200001483A patent/ES2184561B1/en not_active Expired - Fee Related
-
2001
- 2001-06-12 WO PCT/ES2001/000241 patent/WO2001095887A1/en active Application Filing
- 2001-06-12 AU AU74116/01A patent/AU7411601A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3784553A (en) * | 1972-01-17 | 1974-01-08 | Made Labor Sa | Pyridoxine alpha-ketoglutarate and its derivatives |
| BE1010972A6 (en) * | 1996-10-09 | 1999-03-02 | Lupin Lab Ltd | Pharmaceutical anti-tuberculosis composition and method intended to produce said composition |
| RO114406B1 (en) * | 1997-12-12 | 1999-04-30 | Univ De Vest Vasile Goldis | Drug for treating tuberculosis and process for preparing the same |
Non-Patent Citations (3)
| Title |
|---|
| DATABASE HCAPLUS [online] CHEMICAL ABSTRACTS SERVICE (COLUMBUS, OHIO, USA); 30 April 1999 (1999-04-30), accession no. STN Database accession no. 2001:174472 * |
| DATABASE WPI Derwent World Patents Index; XP002905581 * |
| VED S. ET AL.: "Stability of rifampicin in the presence of isoniazide and pyridoxine hydrochloride in liquid dosage form", EAST, PHARM., vol. 33, no. 389, 1990, pages 155 - 156, ISSN 0012-8872 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011034462A1 (en) * | 2009-09-16 | 2011-03-24 | Открытое Акционерное Общество "Xиmиko-Фapmaцebtичeckий Комбинат "Akpиxиh" | Combined anti-tuberculosis preparation |
| EA020961B1 (en) * | 2009-09-16 | 2015-03-31 | Открытое акционерное общество "Химико-фармацевтический комбинат "Акрихин" | Combined anti-tuberculosis preparation |
| CN101785771A (en) * | 2010-03-05 | 2010-07-28 | 张徐红 | Compound isoniazid tablet |
| FR2963236A1 (en) * | 2010-07-28 | 2012-02-03 | Pharma 5 Lab | Preparing composition containing e.g. rifampicin, and optionally ethambutol, comprises wet granulation of isoniazid, pyrazinamide and optionally ethambutol by wetting with binder in solvent, drying and adding rifampicin |
| WO2012013756A3 (en) * | 2010-07-28 | 2012-03-29 | Laboratoires Pharma 5 | Method for preparing tablets combining rifampicin, isoniazid, pyrazinamide and, optionally, ethambutol |
| CN103816545A (en) * | 2013-10-30 | 2014-05-28 | 安徽万邦医药科技有限公司 | Pharmaceutical composition containing rifampicin and sodium dodecyl sulfate |
| WO2015107375A1 (en) | 2013-12-20 | 2015-07-23 | Vergara Campillo Ramiro Moises | Combination of pyridoxine, folic acid and magnesium ions for treating cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2184561B1 (en) | 2003-12-16 |
| AU7411601A (en) | 2001-12-24 |
| ES2184561A1 (en) | 2003-04-01 |
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