CN102727459A - A formulation having first and second active agents - Google Patents

Abstract

The invention relates to a preparation with a first active medicament and a second active medicament and application thereof in preparing medicaments for treating type II diabetes.

Description

A formulation having first and second active agents

technical field

The present invention relates to a preparation with a first and a second active drug and its use in the preparation of a medicament for type II diabetes. the

Background technique

A number of techniques have been used to provide controlled-release and sustained-release drug dosage forms to maintain therapeutic serum levels of the drug and to reduce the effects of drug underdosing due to lack of patient compliance. For example, the prior art has disclosed sustained release tablets having an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing water-soluble components in body fluids such as gastrointestinal fluids to permeate through the coating and dissolve the active ingredient, so that the resulting drug solution can be released through channels in the coating. Alternatively, if the active ingredient is insoluble in the permeate, it can be passed through the channels by a swelling agent such as a hydrogel. Some representative examples of these osmotic tablet systems are disclosed in US Patent Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and 4,783,337. U.S. Patent No. 3,952,741 discloses an osmotic device in which the active agent is released from a core surrounded by a semi-permeable membrane only after there has been sufficient pressure within the membrane to crack or rupture the membrane over a weakened portion of the membrane . the

Currently, efforts have been made to modify the basic osmotic devices described in the above cited patents to provide better controlled release of the active ingredient. For example, US Patent Nos. 4,777,049 and 4,851,229 describe osmotic dosage forms comprising a semipermeable membrane surrounding a core. The core contains an active ingredient and a modulator, wherein the modulator causes the active ingredient to be released in a pulsatile manner through channels in the semipermeable membrane. Further improvements include modifying the semipermeable membrane surrounding the active core, such as changing the ratio of membrane-forming components as described in U.S. Patent Nos. 5,178,867, 4,587,117 and 4,522,625, or increasing the wrapping The number of coatings on the active core. the

Certain controlled release or sustained release formulations using antihyperglycemic drugs such as metformin hydrochloride have been limited to the use of bulking or gelling agents to control the release of the drug from the dosage form. This limited study is exemplified by the publication of WO96/08243 and GLUCOPHAGE™ XR, a controlled release product of metformin hydrochloride available from Bristol-Myers Squibb Co. the

Thiazolidinedione derivatives have been described in US Patent No. 4,687,777. The therapeutic effect of these compounds in combination therapy has been further described in US Patent Nos. 5,859,037; 5,952,356; 5,965,584; 6,150,384 and 6,172,090. the

The use of pharmaceutical dosage forms comprising combinations of antihypertensive drugs and thiazolidinedione derivatives has been disclosed in the art. For example, EPOO 749751 (which is incorporated herein by reference) discloses pharmaceutical compositions comprising an insulin sensitizer, which may be a thiazolidinedione compound, and comprising other antidiabetic agents. More particularly, EPOO 749751 discloses that a preferred insulin sensitizer is pioglitazone, which can be combined with other antidiabetic drugs such as metformin, phenformin or butylbiguanide, and further these drugs can be combined with conventional excipients (mixing and/or coating) to provide odor masking or sustained release. Another example of a combination of an antihyperglycemic drug and a thiazolidinedione derivative is US Patent No. 6,011,049 (herein incorporated by reference). This patent discloses a single pharmaceutical composition comprising pioglitazone or troglitazone and metformin in a sustained release form such as an osmotic pump or a dermal patch. Other combinations of antihyperglycemic agents and thiazolidinedione derivatives can be found in US Patent Nos. 6,524,621; 6,475,521; 6,451,342 and 6,153,632 and PCT Patent Applications WO01/3594 and WO01/3594. the

Also known in the art are WO 99/47125 and US Patent No. 6,099,862 which disclose metformin osmotic tablets coated with an immediate release coating comprising an antihyperglycemic or hypoglycemic drug. the

CN100544717C discloses a pharmaceutical dosage form with first and second active drugs, which adopts the conventional technology of low-viscosity water-soluble adhesives, and does not creatively involve high-viscosity or water-insoluble adhesives. the

Contents of the invention

The content of the present invention is to provide a kind of preparation with first and second active drug, described preparation comprises:

a) a controlled release tablet core containing an antihyperglycemic drug and at least one pharmaceutically acceptable excipient; and

b) An immediate release coating comprising an immediate release second active drug and a highly viscous water soluble or water insoluble binder. the

Preferably, the first active drug is metformin and a pharmaceutically acceptable salt thereof, or the second active drug is pioglitazone and a pharmaceutically acceptable salt thereof. the

Further preferably, the preparation includes:

a) Controlled-release tablet core, which contains about 60%-90% of the first active drug, 5%-40% of binder, 0-20% of absorption enhancer and 0-3% of lubricant;

b) semi-permeable membrane;

c) an immediate-release coating layer, which contains: the second active drug, a high-viscosity water-soluble binder or a water-insoluble binder, and an absorption promoter or a surfactant. the

Further preferably, the highly viscous water-soluble adhesive has a viscosity greater than 6 mPa.s when measured as a 2% aqueous solution at 20°C. the

Further preferably, the binder of the immediate release layer is hydroxypropylmethylcellulose or acrylic resin. the

The pharmaceutical preparation provided by the invention overcomes the technical prejudice in the prior art, boldly adopts unconventional adhesives, and achieves comparable or even better drug-making effect and drug performance than the prior art. the

Detailed ways

The examples provided below are for illustration only and not meant to be limiting. the

Embodiment 1 comprises the preparation of 33.07mg pioglitazone hydrochloride (30mg in terms of pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

Preparation:

1. Prepare 1-5% PVP K90 into a 15% aqueous solution, mix the remaining PVP with metformin hydrochloride, prepare the above mixture into granules by wet granulation process and press into tablet cores;

2. Preparation of semi-permeable membrane coating solution: first prepare cellulose acetate into a clear acetone solution, polyethylene glycol 400 into a clear aqueous solution, mix the two solutions, stir until a clear solution, and set aside;

3. Preparation of immediate-release layer coating solution: Dissolve NaCl in a small amount of water and add 95% ethanol, then add HPMC and pioglitazone hydrochloride respectively, and disperse to prepare the coating solution;

4. Use a laser drilling machine to punch a hole on the upper and lower sides of the core;

5. After coating, place it at 40°C for 24 hours, then take it out. the

Determination of Metformin Hydrochloride Release Rate:

Get the sample, according to the assay method of release rate, adopt the first method of appendix XD of Chinese Pharmacopoeia 2005 edition two, the device of dissolution assay method first method, take 0.1N hydrochloric acid solution 900mL as release medium, rotating speed is 100rpm, operate according to law , take points at 2, 4, 8, and 12 hours, and use high-performance liquid chromatography to measure the release rate. The release data of the drug is as follows: 

Determination of the dissolution rate of pioglitazone hydrochloride:

Get the sample, according to the assay method of release rate, adopt the first method of appendix XD of Chinese Pharmacopoeia 2005 edition two, the device of dissolution assay method first method, take 0.1N hydrochloric acid solution 900mL as release medium, rotating speed is 50rpm, operate according to law , at the 15th, 30th, and 45th minute points were taken, and the release rate was measured by high performance liquid chromatography. The dissolution results of the drug were as follows: 

15min 94.8%

30min 98.6%

45min 98.9%

Embodiment 2 comprises the preparation of 33.07mg pioglitazone hydrochloride (30mg as pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

Preparation:

1. The preparation of tablet core and semipermeable membrane is the same as in Example 1. the

2. Preparation of immediate-release layer coating solution: Dissolve polyethylene glycol 4000 in a small amount of water and add 95% ethanol, then add HPMC and pioglitazone hydrochloride respectively, and disperse to prepare the coating solution;

3. Use a laser drilling machine to punch a hole on the upper and lower sides of the core;

4. After coating, place it at 40°C for 24 hours, then take it out. the

Determination of Metformin Hydrochloride Release Rate:

Assay method is the same as embodiment 1, and its release data are as follows:

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 85.2%

30min 99.5%

45min 98.7%

Embodiment 3 comprises the preparation of 33.07mg pioglitazone hydrochloride (30mg in terms of pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

Preparation:

1. Prepare 1-5% of PVP K30 into a 30% aqueous solution, mix the remaining PVP with metformin hydrochloride, prepare the above mixture into granules by wet granulation process and press into tablet cores;

2. Preparation of semi-permeable membrane coating solution: first prepare cellulose acetate into a clear acetone solution, polyethylene glycol 4000 into a clear aqueous solution, mix the two solutions, stir until a clear solution, and set aside;

3. Preparation of immediate-release layer coating solution: Dissolve polyethylene glycol 6000 in a small amount of water and add 95% ethanol, then add HPMC and pioglitazone hydrochloride respectively, and disperse to prepare the coating solution;

4. Use a laser drilling machine to punch a hole on the upper and lower sides of the core;

5. After coating, place it at 40°C for 24 hours, then take it out. the

Determination of Metformin Hydrochloride Release Rate:

Assay method is the same as embodiment 1, and its release data are as follows:

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 55.2%

30min 85.7%

45min 97.6%

Embodiment 4 comprises the preparation of 33.07mg pioglitazone hydrochloride (30mg in terms of pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

Preparation:

1. The preparation of tablet core and semipermeable membrane is the same as in Example 3. the

2. Preparation of immediate-release layer coating solution: dissolve NaCl in an appropriate amount of water, dissolve acrylic resin E100 in 95% ethanol, mix the two, and then disperse pioglitazone hydrochloride in it to prepare the coating solution;

3. Use a laser drilling machine to punch a hole on the upper and lower sides of the core;

4. After coating, place it at 40°C for 24 hours, then take it out. the

Determination of Metformin Hydrochloride Release Rate:

Detection method is the same as embodiment 1, and its release data is as follows:

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 95.4%

30min 98.6%

45min 99.4%

Embodiment 5 comprises the preparation of 33.07mg pioglitazone hydrochloride (30mg in terms of pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

Preparation:

1. The preparation of tablet core and semipermeable membrane is the same as in Example 3. the

2. Preparation of immediate-release layer coating solution: dissolve lactose in an appropriate amount of water, dissolve acrylic resin E100 in 95% ethanol, mix the two, and then disperse pioglitazone hydrochloride in it to prepare the coating solution;

3. Use a laser drilling machine to punch a hole on the upper and lower sides of the core;

4. After coating, place it at 40°C for 24 hours, then take it out. the

Determination of Metformin Hydrochloride Release Rate:

Detection method is the same as embodiment 1, and its release data is as follows:

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 89.5%

30min 95.7%

45min 96.8%

Embodiment 6 comprises the preparation of 33.07mg pioglitazone hydrochloride (30mg in terms of pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

(a) controlled release tablet core is the same as embodiment 5

(b) semipermeable membrane is the same as embodiment 5

(c) Immediate release coating layer

Pioglitazone Hydrochloride 30.0%

Acrylic resin E100 70.0%

Preparation method: with embodiment 5

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 56.5%

30min 89.8%

45min 99.6%

Embodiment 7 comprises the preparation of 16.54mg pioglitazone hydrochloride (15mg in terms of pioglitazone) and 1000mg metformin hydrochloride controlled release tablet

(a) controlled release tablet core is the same as embodiment 5

(b) semipermeable membrane is the same as embodiment 5

(c) Immediate release coating layer

Pioglitazone Hydrochloride 70.0%

Acrylic resin E100 30.0%

Preparation method: with embodiment 5. the

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 95.5%

30min 96.7%

45min 96.8%

Embodiment 8 comprises the preparation of 16.54mg pioglitazone hydrochloride (15mg in terms of pioglitazone) and 500mg metformin hydrochloride controlled release tablet

Preparation method: with embodiment 5.

Determination of Metformin Hydrochloride Release Rate:

Detection method is the same as embodiment 1, and its release data is as follows:

Determination of the dissolution rate of pioglitazone hydrochloride:

Assay method is with embodiment 1, and its stripping result is as follows:

15min 92.3%

30min 96.7%

98.8% in 45 minutes.

Claims (10)

1. pharmaceutical preparation with first and second active medicines, said preparation comprises:

A) sustained release label, it contains hyperglycemia medicine and at least a pharmaceutically acceptable excipient; With

B) rapid release coatings, this coatings comprise second active medicine and high viscosity water-soluble binder or the water insoluble adhesive that discharges immediately.

2. pharmaceutical preparation according to claim 1 is characterized in that, said first active medicine is metformin and pharmaceutically acceptable salt thereof.

3. pharmaceutical preparation according to claim 1 is characterized in that, said second active medicine is pioglitazone and pharmaceutically acceptable salt thereof.

4. pharmaceutical preparation according to claim 2 is characterized in that, said first active medicine is a metformin hydrochloride.

5. pharmaceutical preparation according to claim 3 is characterized in that, said second active medicine is a pioglitazone hydrochloride.

6. according to any described pharmaceutical preparation of claim 1～5, it is characterized in that said preparation comprises:

A) sustained release label wherein comprises about 60%～90% first active medicine, 5%～40% binding agent, 0～20% absorption enhancer and 0～3% lubricant;

B) semipermeable membrane;

C) rapid release coatings, this coatings contains: second active medicine, high viscosity water-soluble binder or water insoluble adhesive and absorption enhancer or surfactant.

7. pharmaceutical preparation according to claim 6 is characterized in that, said high viscosity water-soluble binder at 20 ℃ during as 2% determination of aqueous solution, has the viscosity greater than 6mPas.

8. pharmaceutical preparation according to claim 5, wherein said high viscosity water-soluble binder is a hydroxypropyl methylcellulose.

9. pharmaceutical preparation according to claim 5, wherein said water insoluble adhesive are acrylic resin.

10. according to the application of any described pharmaceutical preparation of claim 1～9 in the medicine of preparation treatment type ii diabetes.