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WO1999030714A1 - Preparation de theophylline a liberation prolongee et procede de fabrication associe - Google Patents

Preparation de theophylline a liberation prolongee et procede de fabrication associe Download PDF

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Publication number
WO1999030714A1
WO1999030714A1 PCT/JP1998/005471 JP9805471W WO9930714A1 WO 1999030714 A1 WO1999030714 A1 WO 1999030714A1 JP 9805471 W JP9805471 W JP 9805471W WO 9930714 A1 WO9930714 A1 WO 9930714A1
Authority
WO
WIPO (PCT)
Prior art keywords
theophylline
sustained
lauryl sulfate
sodium lauryl
tablet
Prior art date
Application number
PCT/JP1998/005471
Other languages
English (en)
Japanese (ja)
Inventor
Mutsuo Okumura
Masaaki Sunohara
Tadashi Ukigaya
Original Assignee
Nikken Chemicals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nikken Chemicals Co., Ltd. filed Critical Nikken Chemicals Co., Ltd.
Publication of WO1999030714A1 publication Critical patent/WO1999030714A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to a sustained-release tablet of theophylline, and more particularly, to a small-sized and inexpensive sustained-release tablet of theophylline.
  • Theofirin is a useful drug that is commonly used as a symptomatic treatment for bronchial asthma.
  • theophylline has a narrow effective blood concentration range.
  • the theophylline sustained release formulations are insoluble.
  • a type in which a medicinal ingredient is dispersed in a matrix composed of a synthetic resin or lipid to make sustained release for example, Japanese Patent Application Laid-Open No. Sho 56-122321, US Patent No.
  • capsules and tablets contain several types of small particles (beads) with different release rates. These small particles are composed of an active ingredient layer and an insoluble lipid layer around the core. Are alternately formed (see, for example, US Pat. No. 3,872,998).
  • the ratio of the carrier and excipients for dispersing the active ingredient reaches 50% or more of the active ingredient, so that the decrease in the active ingredient content and the size of the tablet can be avoided.
  • the release of the medicinal component is incomplete.
  • the latter type of preparation has drawbacks such as requiring a high degree of skill because of the complicated operation required for its preparation, and increasing the production cost.
  • the former is a non-disintegrating thin plate-like tablet consisting almost exclusively of theophylline.
  • the tablet containing only theophylline has a poor dissolution property, and there is a concern that the absorption amount is reduced.
  • the latter is a tablet obtained by compression-molding a mixture consisting essentially of theophylline and ethylcellulose by a direct compression method.
  • this tablet when it is a small tablet containing 50 to 20 Omg of theophylline, shows almost the same absorption amount as that of the known formulation. Large tablets containing the above components have incomplete dissolution in the gastrointestinal tract, resulting in reduced absorption and sufficient blood Medium concentration cannot be maintained. Disclosure of the invention
  • a theophylline sustained-release tablet comprising, as main components, theophylline and sodium lauryl sulfate.
  • the present invention also includes compression-molding a uniform mixture containing theophyrin and sodium lauryl sulfate as main components by a direct hitting method. And a method for producing a theophylline sustained-release tablet.
  • Fig. 1 is a graph showing the results of a dissolution test (Method 2, 50 rotations, 1 JP solution) of the tablets obtained in Examples 1 to 4 and Reference Example 1.
  • FIG. 2 is a graph showing the results of a dissolution test (the second method, 50 rotations, two liquids in Japan) of the tablets obtained in Examples 1 to 4 and Reference Example 1.
  • the present inventors have found that when the lubricant is added to Teofirin alone or to Teofirin in an amount of 1% by weight or less and tableted, the dissolution of Teofirin becomes surprisingly poor.
  • the use of highly water-soluble saccharides (sucrose, lactose, etc.) and disintegrating additives (corn starch, etc.) to promote the dissolution of theophylline for the purpose of controlling the dissolution greatly increases the effect of diet. It was also found that they would receive it. Therefore, once-daily administration of a tablet with a high content of theophylline is effective in absorbing theophylline.
  • the present invention relates to a theophylline sustained release tablet comprising theophylline and sodium lauryl sulfate, and more particularly, to theophylline and sodium lauryl sulfate.
  • Theophylline is obtained by direct compression (direct powder compression method) of a homogeneous mixture consisting of, without granulation, humidification, and heat treatment. Tablet.
  • the ratio of sodium lauryl sulfate to theophylline in the tablet is preferably from 0.1 to 20 parts by weight of sodium lauryl sulfate to 100 parts by weight of theophylline. It is 1.0 to 10 parts by weight ⁇ 5 '.
  • the above-mentioned theophylline sustained-release tablet contains the theofilin and sodium lauryl sulfate in a ratio of 100 parts by weight of theophylline to 100 parts by weight of theophylline.
  • Sodium sodium lauryl sulfate is added in an amount of 0.5 to 10 parts by weight, preferably 1.0 to 10 parts by weight, and if necessary, a small amount of an additive is added thereto.
  • the mixture can be prepared by compression molding to a desired size by a direct hitting method.o
  • theophylline used in the present invention a commercially available powdered product is usually used as it is or is appropriately pulverized. If desired, the product is prepared in advance into a theophylline granule by a dry method. Can also be used.
  • sodium lauryl sulfate is uniformly mixed with the above-mentioned theophylline. Any substance that can be used can be used, and those described in the Japanese Pharmacopoeia can be used.
  • the dissolution rate of theophylline in the theophylline sustained-release tablet of the present invention is mainly determined by changing the mixing ratio of sodium rauryl sulfate to theophylline. Can be adjusted.
  • the mixing ratio of sodium rauryl sulfate to theophyline is set to 100 parts by weight of thelauryl to the amount of lauryl. It is desirable to use 0.1 to 20 parts by weight of sodium sulfate, preferably 1.0 to 10 parts by weight.
  • the mixing ratio of sodium lauryl sulfate is more than the above range, the elution rate of theofilin becomes too fast to obtain a predetermined sustained-release effect, and it is less than the above range. If it becomes too small, the elution of theophylline becomes insufficient, and it becomes difficult to obtain a desired sustained release effect.
  • the theophylline sustained-release tablet of the present invention is basically composed of theophylline and sodium lauryl sulfate, and may further contain an excipient and a lubricant, if necessary. And other additives can be appropriately compounded. The amount of such an additive may be used as long as it does not significantly affect the dissolution of theophylline, and the ratio of the additive to the whole tablet is about 25% by weight or less. These additives are used for the purpose of improving the moldability, binding property and tableting property, if necessary, when formulating by compression molding.
  • the excipient include lactose, sucrose, glucose, mannite, and the like.
  • the lubricant include magnesium stearate, calcium stearate, light gay anhydride, and hydrous dioxide. Silicon or the like is used.
  • the method for producing the theophylline sustained release tablet according to the present invention is not particularly limited, but preferably, a uniform mixture of theophylline and sodium lauryl sulfate is subjected to a direct punching method. Manufactured by compression molding more directly I do. Compared with other tablet molding methods, the Manpo method can omit intermediate steps such as condylarization, is extremely simple in operation, and is advantageous in terms of time and economy.
  • the size of the obtained tablet is significantly smaller than that of a conventional theophylline-containing preparation. It has the advantage of being able to be in a form, and furthermore, the elution rate of theophylline is not affected by the pH of the digestive fluid or enzymes, the elution rate is high, and the elution rate is high. The advantage is that the elution of the phosphorus is almost complete. Also, when this is actually administered orally to humans, it suppresses excessive increase in the blood concentration of Teofirin immediately after administration, promptly reaches the optimum blood concentration, and extends the Tephrin for a long time. Because it can maintain a stable and effective blood concentration, the frequency of administration can be 1-2 times a day.
  • the dose of theophylline is generally 200 to 400 mg / day / person.o
  • Example 2 80 g of theophylline, sodium sodium lauryl sulfate;;: g, 0.82 g of calcium stearate, 0.4 g of hydrous silicon dioxide are placed in a container, and each component is placed in a container. was uniformly mixed, and then compression-molded with a modified punch at 1.0 to 1.5 t to obtain tablets having a weight of 41.7 mg and a thickness of 4.9 mm.
  • the mixture was compression-molded at 1.0 to 1.5 t using a modified punch to give tablets having a weight of 49.7 mg and a thickness of 5.7 mm.
  • theophylline 80 g of theophylline, 8 g of low-substituted hydroxypropyl cellulose, 4 g of sodium raurylsulfate, 0.88 g of calcium stearate, 0.44 g of hydrous silicon dioxide
  • the mixture was placed in a container, and the components were uniformly mixed. After that, the mixture was compression-molded with a modified punch at 1.0 to 1.5 t into a tablet with a weight of 467 mg and a thickness of 5.5 mm.
  • JP Japanese Pharmacopoeia
  • Tablets prepared in Examples 1 to 4 and Reference Example 1 were used as samples according to the second method (paddle method) of the dissolution test method.
  • the dissolution test was conducted using the first test solution (hereinafter abbreviated as “1st JP solution”) and the 2nd test solution (hereinafter abbreviated as “2nd JP solution”) of the JP Disintegration Test.
  • 1st JP solution the first test solution
  • 2nd JP solution hereinafter abbreviated as “2nd JP solution” of the JP Disintegration Test.
  • the eluate of each sample was collected over time.
  • the absorbance at 27 lnm is used to remove the sample.
  • the amount of eluted lin was calculated. The results are not shown in FIGS.
  • T max time to reach maximum blood concentration
  • a U C Area under the blood concentration curve
  • the kinetic parameters of the drug are shown in Table 2.
  • the AUC and C max when the tablet of the present invention was orally administered at the time of fasting were two tablets of commercially available Theodor Tablet 200 (Niken Kagaku Co., Ltd.). Results after administration (eg, Kazuo Kawakatsu, Shoji Takeyama, Mitsuru Kawaai Allergy, 37, 256 (1988) ".
  • the sustained release tablet of aofirin of the present invention can suppress an excessive increase in the blood concentration of theophylline immediately after administration, and can quickly reach the optimal blood concentration. Furthermore, it can be manufactured more compactly and inexpensively than conventional ones, is not easily affected by diet, and can maintain a stable effective blood concentration of theofilin for a long time.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Préparation de théophylline à libération prolongée et procédé de fabrication associé, qui consiste à mouler par compression un mélange homogène comprenant principalement de la théophylline et du laurylsulfate de sodium, sans granulation ni humidification ni traitement thermique.
PCT/JP1998/005471 1997-12-17 1998-12-04 Preparation de theophylline a liberation prolongee et procede de fabrication associe WO1999030714A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/363718 1997-12-17
JP36371897A JP4221068B2 (ja) 1997-12-17 1997-12-17 テオフィリン徐放性錠剤及びその製造方法

Publications (1)

Publication Number Publication Date
WO1999030714A1 true WO1999030714A1 (fr) 1999-06-24

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PCT/JP1998/005471 WO1999030714A1 (fr) 1997-12-17 1998-12-04 Preparation de theophylline a liberation prolongee et procede de fabrication associe

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JP (1) JP4221068B2 (fr)
WO (1) WO1999030714A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089573A1 (fr) * 2000-05-24 2001-11-29 Otsuka Pharmaceutical Co., Ltd. Procede servant a stabiliser une preparation
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
US8685444B2 (en) 2002-09-20 2014-04-01 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and methods
US8846104B2 (en) 2006-06-19 2014-09-30 Alpharma Pharmaceuticals Llc Pharmaceutical compositions for the deterrence and/or prevention of abuse

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA200403281B (en) * 2001-11-07 2005-12-13 Synthon Bv Tamsulosin tablets.
CN110898019A (zh) * 2019-12-19 2020-03-24 上海宣泰海门药业有限公司 多索茶碱片及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59170012A (ja) * 1983-03-07 1984-09-26 チバ・ガイギ−・アクチエンゲゼルシヤフト 一定の溶出特性を有する医薬組成物及びその製造法
JPS59210022A (ja) * 1983-04-09 1984-11-28 Nikken Kagaku Kk テオフイリン徐放性製剤
WO1995021607A1 (fr) * 1994-02-14 1995-08-17 Andrx Pharmaceuticals, Inc. Composition sous forme d'hydrogel a liberation prolongee regulee

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59170012A (ja) * 1983-03-07 1984-09-26 チバ・ガイギ−・アクチエンゲゼルシヤフト 一定の溶出特性を有する医薬組成物及びその製造法
JPS59210022A (ja) * 1983-04-09 1984-11-28 Nikken Kagaku Kk テオフイリン徐放性製剤
WO1995021607A1 (fr) * 1994-02-14 1995-08-17 Andrx Pharmaceuticals, Inc. Composition sous forme d'hydrogel a liberation prolongee regulee

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089573A1 (fr) * 2000-05-24 2001-11-29 Otsuka Pharmaceutical Co., Ltd. Procede servant a stabiliser une preparation
KR100741937B1 (ko) * 2000-05-24 2007-07-24 오츠카 세이야쿠 가부시키가이샤 제제의 안정화 방법
CN100377746C (zh) * 2000-05-24 2008-04-02 大塚制药株式会社 制剂的稳定化方法
US7867514B2 (en) 2000-05-24 2011-01-11 Otsuka Pharmaceutical Co., Ltd. Method for stabilizing preparation
JP4902928B2 (ja) * 2000-05-24 2012-03-21 大塚製薬株式会社 製剤の安定化方法
US8685444B2 (en) 2002-09-20 2014-04-01 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and methods
US8685443B2 (en) 2002-09-20 2014-04-01 Alpharma Pharmaceuticals Llc Sequestering subunit and related compositions and methods
US8846104B2 (en) 2006-06-19 2014-09-30 Alpharma Pharmaceuticals Llc Pharmaceutical compositions for the deterrence and/or prevention of abuse
US8877247B2 (en) 2006-06-19 2014-11-04 Alpharma Pharmaceuticals Llc Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition

Also Published As

Publication number Publication date
JPH11180875A (ja) 1999-07-06
JP4221068B2 (ja) 2009-02-12

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