WO2005030201A1 - Preparation a liberation prolongee contenant de l'hydrochlorothiazide et du carvedilol/atenolol - Google Patents

Preparation a liberation prolongee contenant de l'hydrochlorothiazide et du carvedilol/atenolol Download PDF

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Publication number
WO2005030201A1
WO2005030201A1 PCT/CN2003/000822 CN0300822W WO2005030201A1 WO 2005030201 A1 WO2005030201 A1 WO 2005030201A1 CN 0300822 W CN0300822 W CN 0300822W WO 2005030201 A1 WO2005030201 A1 WO 2005030201A1
Authority
WO
WIPO (PCT)
Prior art keywords
release
atenolol
dihydrochlorothiazide
carvedilol
free base
Prior art date
Application number
PCT/CN2003/000822
Other languages
English (en)
Chinese (zh)
Inventor
Shuyi Zhang
Jin Wang
Original Assignee
Shuyi Zhang
Jin Wang
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 Shuyi Zhang, Jin Wang filed Critical Shuyi Zhang
Priority to AU2003272851A priority Critical patent/AU2003272851A1/en
Priority to PCT/CN2003/000822 priority patent/WO2005030201A1/fr
Publication of WO2005030201A1 publication Critical patent/WO2005030201A1/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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a free base containing dihydrochlorothiazide and carvedilol or atenolol or atenolol or a pharmaceutically acceptable salt thereof.
  • Compound slow-release formula especially the dissolution method of compound slow-release formula containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof, so it is more convenient to take, has low side effects, and Has better tolerance and patient compliance.
  • U.S. Patent No. 4,503,067 discloses carvedilol common tablet formulations.
  • Carvedilol (trade name Core g ), which is currently sold in the United States, is a commonly used oral tablet, and the dosage is twice a day.
  • C 0 reg is currently the only approved light can be used to reduce moderate to severe heart failure patients at risk of death ⁇ - blockers. It is also approved for treating patients with hypertension accompanied by diabetes and high cholesterol. Core is also the only beta-blocker currently approved to reduce the risk of death in patients who have had a recent heart attack and who have low heart function, whether or not they have symptoms of heart failure.
  • 0) 1 " ⁇ includes 4.125mg, 6.25mg, 12.5mg and 25mg four dose tablets.
  • Carvedilol can be quickly and widely absorbed through the oral route, and its bioavailability is approximately 25-35% due to first-pass metabolism.
  • the oral half-life of carvedilol is usually 7 to 10 hours.
  • Patent W099 / 24017 discloses a controlled release (sustained release) matrix tablet of carvedilol.
  • the preparation consists of two parts, one is the immediate release part in the coating film, and the other is the controlled or sustained release part in the tablet core.
  • This matrix tablet contains excipients such as hydroxypropyl methylcellulose (HPMC), Kappabo, and mannitol.
  • HPMC hydroxypropyl methylcellulose
  • Kappabo mannitol
  • Sodium carboxymethyl starch This disintegrant is commonly used in the formulation of immediate release formulations or pH-dependent coating formulations. Disintegrants allow tablets to accelerate drug release through disintegration. And too fast release of the drug may have side effects.
  • Tablets are usually prepared with a coating method (pH-dependent or slow-release coating film), but once a coating problem occurs, such a operation cannot make a complete tablet.
  • Specific viscosity is usually not described in detail in the description of hydrophilic polymers such as HPMC. HPMC with different viscosities will release the drug in an immediate or slow release manner.
  • the present invention does not specifically describe data on the release rate of carvedilol matrix tablets in vitro or in vivo pharmacokinetics.
  • U.S. Patent Nos. 4,389,393 and 4,968,508 also disclose the invention of Carvedilol controlled release or sustained release matrix tablets.
  • Other related Carvedilol controlled-release or sustained-release formulations in U.S. patents Nos. 4524060, 4943401, 4880830 and 5068112 are introduced. However, these formulations are not suitable for making daily doses.
  • Atenolol is a synthetic selective beta ⁇ (cardioselective) adrenergic blocker. Atenolol has a molecular weight of 266, a solubility of 26.5mg ml at 37 ° C, a partition coefficient of 0.23 (octanol / 7jO, easily soluble in 1N HCL (25 ° C, 300mg / ml), and chloroform (25 ° C, 3 mg / mO slightly soluble.
  • TENORMIN is the trade name of atenolol.
  • the drug is available in 25 mg, 50 mg and 100 mg oral tablets.
  • Atenolol's oral tablets are rapidly absorbed, and approximately 50% of the oral dose is absorbed, and the remaining original drug is excreted in the feces. After 2 to 4 hours of administration, the plasma drug concentration reached a peak. The half-life of oral TENORMIN is approximately 6-7 hours. Slow administration can maintain the same pharmacokinetic profile of 50 mg and 100 mg oral tablets—both blocking and hypotensive effects are maintained for at least 24 hours.
  • TENORMIN can be taken alone or daily with a diuretic.
  • TENORJiHN can effectively control blood pressure. It can be used alone or in combination with other antihypertensive drugs, especially thiazide diuretics.
  • TENORMIN has a long-term effect on patients with angina pectoris and also has an effect on acute myocardial infarction.
  • Dihydrochlorothiazide is a thiazide (diuretic) that is taken once a day. It has been reported using both ⁇ -blockers and thiazides treatment of hypertension, congestive heart failure and angina has a good effect (McTavish et al, 1993, Drugs45 (2):. 232-258) 0 but The compound formula has not been greatly improved in dosage form. In the experimental study, it was only just to mix two single-drug tablets for patients to take. US Patent No. 6403579 has disclosed a synthesis and production process of carvedilol and dichlorochlorothiazide compound preparations. This patent describes a compound immediate release formulation of carvedilol and dihydrochlorothiazide.
  • the present invention relates to a compound sustained-release preparation of carvedilol free base, a main component of dihydrochlorothiazide and CoregTt, or atenolol or a pharmaceutically acceptable salt thereof. Summary of the invention:
  • the novelty of the present invention is to propose a compound sustained-release formulation containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof.
  • the purpose of the present invention is to greatly improve the therapeutic effect of treating hypertension, congestive heart failure and angina pectoris with low side effects.
  • the invention also proposes a specific formula, namely a compound slow-release formula containing dihydrochlorothiazide and carvedilol free base or atenolol or its pharmaceutically acceptable salts, which can effectively improve the treatment of hypertension and congestive heart failure And the efficacy of angina pectoris.
  • the object of the present invention is also to propose a new administration method and dosage form of carvedilol base or atenolol, so as to significantly improve the clinical efficacy of daily dosage of hypertension, congestive heart failure and angina pectoris. .
  • the present invention aims to prepare dihydrochlorothiazide and carvedilol base or atenolol or atenolol as a compound sustained-release preparation.
  • the compound sustained-release solid dosage form of dihydrochlorothiazide and carvedilol or atenolol or atenolol medicinal salts according to the present invention can be operated according to conventional procedures, including granulation, mixing, ebullating bed, Granulation, tableting, dry granulation, crushing, packaging into capsules and coating.
  • the compound sustained-release preparations of dihydrochlorothiazide and carvedilol or atenolol or atenolol medicinal salts according to the present invention include two dosage forms of tablets and capsules.
  • the matrix sustained-release tablets of the present invention can be made of two materials: (1) polymers of all hydrophilic cellulose derivatives, and / or (2) various aliphatic compounds such as various waxes (such as Brazil Palm wax), glyceryl tristearate, etc.
  • the capsule dosage form of the present invention can be made by techniques such as granulation, spray granulation, polymer coating and the like.
  • Compound sustained-release preparations of dihydrochlorothiazide and carvedilol or atenolol or atenolol medicinal salts can be enteric-coated (enteric polymer) drug particles, granules, pellets, or tablets Method made.
  • enteric polymers are acid-resistant but easily soluble in solvents with a basic pH, such as hypromellose phthalate, cellulose acetate monophthalate or cellulose butyrate monoacetate, and polyvinyl acetate phthalate Formate, acrylic polymer Eudragit L and Eudragit S.
  • the coated granules can be filled into capsules or compressed into tablets.
  • the invention particularly proposes a compound drug release library containing dihydrochlorothiazide and carvedilol or atenolol.
  • formulation of the dosage form is compatible with various other drugs or active ingredients such as various soluble, slightly soluble and difficult Soluble ingredients are also effective when mixed together.
  • the present invention is not limited to these identified components, and / or the drug substance or other active ingredients that can be released under certain conditions.
  • the ideal dosage forms in tablets and capsules that is, the sustained-release dosage forms according to the present invention include (1) immediate-release dosage forms containing 0% -50% of dihydrochlorothiazide and carvedilol or atenolol ( 2)
  • the sustained release dosage form contains the remaining ingredients of the drug.
  • the ideal dosage form in tablets and capsules is the carvedilol sustained-release dosage form of the present invention, which does not release more than 50% in the first hour, 30% -90% in the first 8 hours, and release in the first 16 hours.
  • the total amount will not be less than 80%.
  • Such pellets can be prepared by the method described in Example 2 and coated with an ethyl cellulose solution.
  • the ethylcellulose solution formulation is detailed in the table below.
  • the coated pellets are mixed with other ingredients and used for tabletting or direct filling into capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation à libération prolongée pour le traitement de l'hypertension, de l'insuffisance cardiaque congestive et de l'angine de poitrine. Cette préparation contient de l'hydrochlorothiazide et du carvédilol sous forme de base libre, ou bien de l'aténolol ou un sel pharmaceutiquement acceptable de ceux-ci.
PCT/CN2003/000822 2003-09-26 2003-09-26 Preparation a liberation prolongee contenant de l'hydrochlorothiazide et du carvedilol/atenolol WO2005030201A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003272851A AU2003272851A1 (en) 2003-09-26 2003-09-26 Sustained release preparation containing hydrochlorothiazide
PCT/CN2003/000822 WO2005030201A1 (fr) 2003-09-26 2003-09-26 Preparation a liberation prolongee contenant de l'hydrochlorothiazide et du carvedilol/atenolol

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2003/000822 WO2005030201A1 (fr) 2003-09-26 2003-09-26 Preparation a liberation prolongee contenant de l'hydrochlorothiazide et du carvedilol/atenolol

Publications (1)

Publication Number Publication Date
WO2005030201A1 true WO2005030201A1 (fr) 2005-04-07

Family

ID=34383965

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2003/000822 WO2005030201A1 (fr) 2003-09-26 2003-09-26 Preparation a liberation prolongee contenant de l'hydrochlorothiazide et du carvedilol/atenolol

Country Status (2)

Country Link
AU (1) AU2003272851A1 (fr)
WO (1) WO2005030201A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1041103A (zh) * 1987-04-28 1990-04-11 E·R·斯奎布父子公司 小珠状新型药物组合物及形成方法
CN1328460A (zh) * 1998-11-27 2001-12-26 弗·哈夫曼-拉罗切有限公司 药物组合制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1041103A (zh) * 1987-04-28 1990-04-11 E·R·斯奎布父子公司 小珠状新型药物组合物及形成方法
CN1328460A (zh) * 1998-11-27 2001-12-26 弗·哈夫曼-拉罗切有限公司 药物组合制剂

Also Published As

Publication number Publication date
AU2003272851A1 (en) 2005-04-14

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