KR100593795B1 - Formulations for oral administration containing ramipril with improved stability - Google Patents

Abstract

The present invention relates to a formulation for oral administration comprising ramipril with improved stability.

The formulation for oral administration of the present invention can maintain excellent stability of ramipril without changing formulation by using only lactose as an excipient without using other excipients. In addition, even if less than 5% of the content of lactose by replacing other additives can maintain the stability of ramipril equivalently when only lactose as an excipient. Therefore, the formulation for oral administration according to the present invention is superior in stability to conventional commercial formulations, and the manufacturing process is simple and economically useful.

Description

A preparation comprising ramipril improved stability for oral administration

The present invention relates to a formulation for oral administration comprising ramipril with improved stability.

Ramipril; 2- (N-((S) -1-ethoxycarbonyl-3-phenylpropyl) -L-alanine)-(1S, 3S, 5S) -2-azabicyclo (3.3.0) -octane-3- Carboxylic acid] is an inhibitor of angiotensin converting enzyme (ACE) and is used as an antihypertensive agent.

ACE inhibitors, including ramipril, are sensitive to certain types of degradation. Specifically, (1) cyclization by internal nucleophilic attack to form substituted diketopiperazine, (2) hydrolysis of side chain ester groups, and (3) oxidation to form often unnecessarily colored products. Can be decomposed by Therefore, ACE inhibitors, including ramipril, have problems in stability, such as being easily degraded in pharmaceutical dosage forms. Therefore, many studies have been conducted such as the use of stabilizers to overcome these instability problems of ACE inhibitors.

EP 264,888 describes the stabilization of ACE inhibitor-containing pharmaceutical compositions using ascorbic acid alone as a stabilizing component or a combination of ascorbic acid and fumaric acid, maleic acid or citric acid.

US Pat. No. 4,743,450 relates to the stabilization of ACE inhibitor-containing pharmaceutical compositions using a combination of alkali or alkaline earth metal salts (preferably magnesium carbonate) and sugars (preferably mannitol or lactose) as stabilizing components. It is described. However, the magnesium hydroxide used in this patent acts as an effective stabilizer, but has a problem that it is difficult to be formulated into tablets due to the inferior compressibility, moldability, and flowability of magnesium hydroxide. In particular, it is prominent when prepared using the wet granulation method.

Korean Patent Laid-Open Publication No. 10-2001-52557 is a method of improving the wet granulation purification method using magnesium hydroxide, and describes stabilization of an ACE inhibitor-containing composition using magnesium oxide. Specifically, oxidation is achieved by combining magnesium oxide as an ACE inhibitor, a cyclization stabilizer, and a known filler having a hydrolysis minimizing effect against a hydrolysis minimizing agent of the ACE inhibitor, such as sugars, diuretics, dicalcium phosphate or an ACE inhibitor. To prepare a composition resistant to degradation by hydrolysis and cyclization. The use of magnesium oxide not only minimizes cyclization degradation of the ACE inhibitors, but also enhances the ACE inhibitors into pharmaceutical compositions by wet granulation methods.

Korean Patent No. 10-122067 discloses a pharmaceutical composition having enhanced stability to mechanical stress containing ramipril and a polymeric protective film or a buffer and a method for preparing the same. Mechanical stress by protective coating of a polymeric membrane former on susceptible ramipril or by mixing the ramipril with a physiologically acceptable buffer that allows the pH in the formulation to be adjusted within the range of weak acid to weak alkali in the presence of moisture. Inactivation due to this can be suppressed and the ramipril can be stabilized.

Korean Patent No. 10-227156 describes a pharmaceutical composition having improved storage stability and a method for preparing the same by incorporating an acid donor such as glycine hydrochloride as a stabilizer in an ACE inhibitor. This stabilization method protects the ACE inhibitors from degradation, exhibits extended shelf-life under normal storage conditions, is less sensitive to moisture and can improve stability against increase in moisture, less discoloration during shelf life, There is an advantage to less instability when used in the presence of colorants.

However, ramipril is affected by various excipients used when preparing the formulation of the pharmaceutical composition of the patent, causing a problem that the stability is significantly reduced.

Commonly used excipients include sugars such as lactose, sucrose, mannitol and sorbitol; Starches such as corn starch and tapioca starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; Calcium phosphate such as dicalcium phosphate; Sodium sulfate; And polyvinyl alcohol. In addition, the pharmaceutical preparations may contain any of the ingredients conventionally used, which may include lubricants such as talc, alkaline earth metal stearates such as magnesium stearate and calcium stearate, and hydrogenated cottonseed oil. Hydrogenated vegetable oils such as; Binders such as polyvinylpyrrolidone (povidone) and gelatin; And disintegrants such as microcrystalline cellulose, crosslinked polyvinylpyrrolidone and alginic acid. Other optional ingredients include fillers, water removers, buffers, preservatives, antioxidants, colorants, and flavoring agents.

As such, in general, the preparation of the pharmaceutical composition includes many of the various excipients and optional ingredients listed above in addition to the active substance and the stabilizer, and thus the inventors can maintain the stability more easily and effectively. I became interested in

Therefore, the present inventors are studying a method for maintaining the stability of ramipril through a simple manufacturing process without using various excipients, and stability without affecting ramipril in a formulation using only lactose as an excipient in the ramipril active material. In addition, it was confirmed that maintaining the stability of ramipril equivalently to using only lactose as an excipient even if less than 5% of lactose content was replaced with other additives, and completed the present invention.

The present invention is to provide a formulation for oral administration comprising ramipril with improved stability.

The present invention provides a formulation for oral administration comprising ramipril with improved stability.

Hereinafter, the present invention will be described in detail.

Oral dosage form of the present invention is characterized in that it comprises 0.5 to 10% by weight ramipril and 90 to 99.5% by weight lactose.

In addition, the formulation for oral administration of the present invention is characterized in that it comprises 0.5 to 10% by weight of ramipril, 85 to 99.49% by weight lactose and 0.01 to 5% by weight of a pharmaceutically acceptable additive.

The pharmaceutically acceptable additives include one selected from the group consisting of microcrystalline cellulose, mannitol, corn starch, glyceryl bicarbonate, sodium lauryl sulfate, magnesium stearate and talc.

The formulation for oral administration of the present invention is prepared by mixing ramipril and lactose using apple No. 50 and then filling it into capsule No. 3.

After leaving the prepared capsules at a temperature of 40 ° C. and a relative humidity of 75% for 5 months, the content of ramipril was observed. As a result, the content change of the formulation for oral administration consisting of ramipril and lactose according to the present invention was 3.5%. It shows little change in content than the formulation (4.7 ~ 5.8%). In addition, in the case of a formulation in which less than 5% of the lactose content is replaced with other additives, the content is 3.9 to 5.3%, which shows little change in content than commercially available formulations.

Therefore, the formulation for oral administration of the present invention can keep the stability of ramipril excellent without changing the formulation by using only lactose as an excipient without using other excipients, and even if less than 5% of the lactose content is replaced by other additives. By maintaining the stability of ramipril in the same manner as when only lactose was used as an excipient, it can be seen that it is stable under conditions of a temperature of 40 ° C. and a relative humidity of 75%.

The oral preparation of the present invention is preferably in an oral solid form, more preferably a capsule.

In the present invention, the weight of one capsule is about 250 mg, ramipril may comprise 2.5 ~ 10mg. The dosage varies depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion and severity of the disease. The daily dosage of ramipril is about 1.25-10.0mg / kg. More preferably, the administration is divided once or several times a day.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

Example 1  : Preparation of ramipril-containing capsule using lactose (10,000)

50 g of ramipril and 1,950 g of lactose were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Examples 2-8  : Preparation of ramipril-containing capsules using a mixture of lactose and one pharmaceutically acceptable additive (10,000)

Example 2  : Preparation of ramipril-containing capsule using lactose and microcrystalline cellulose (10,000)

50 g of ramipril, 1930 g of lactose and 20 g of microcrystalline cellulose were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Example 3  : Preparation of ramipril-containing capsule using lactose and mannitol (10,000)

50 g of ramipril, 1,930 g of lactose, and 20 g of mannitol were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Example 4  : Preparation of ramipril-containing capsule using lactose and corn starch (10,000)

50 g of ramipril, 1,930 g of lactose and 20 g of corn starch were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Example 5  : Preparation of ramipril containing capsules using lactose and glyceryl bicarbonate (10,000)

50 g ramipril, 1930 g lactose, and 20 g glyceryl bicarbonate were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Example 6  : Preparation of ramipril-containing capsule using lactose and sodium lauryl sulfate (10,000)

50 g ramipril, 1,930 g lactose, and 20 g sodium lauryl sulfate were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Example 7  : Preparation of ramipril-containing capsule using lactose and magnesium stearate (10,000)

50 g ramipril, 1930 g lactose, and 20 g magnesium stearate were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Example 8  : Preparation of ramipril-containing capsule using lactose and talc (10,000)

Capsules were prepared by varying the ratio of lactose and talc.

1. 50 g ramipril, 1930 g lactose and 20 g talc were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

2. 50 g ramipril, 1,910 g lactose and 40 g talc were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

3. 50g ramipril, 1890g lactose and 60g talc were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Examples 1-7  : Preparation of Ramipril-Containing Capsule Using One Pharmaceutically Acceptable Additive

Comparative Example 1  : Preparation of ramipril-containing capsule using microcrystalline cellulose (10,000)

50 g of ramipril and 1,950 g of microcrystalline cellulose were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 2  : Preparation of ramipril-containing capsule using mannitol (10,000)

50 g of ramipril and 1,950 g of mannitol were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 3  : Preparation of ramipril-containing capsule using corn starch (10,000 pieces)

50 g of ramipril and 1,950 g of corn starch were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 4  : Preparation of ramipril-containing capsule using glyceryl bicarbonate (10,000)

50 g of ramipril and 1,950 g of glyceryl bicarbonate were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 5  : Preparation of ramipril-containing capsule using sodium lauryl sulfate (10,000)

50 g of ramipril and 1,950 g of sodium lauryl sulfate were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 6  : Preparation of ramipril-containing capsule using magnesium stearate (10,000)

50 g of ramipril and 1,950 g of magnesium stearate were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 7  : Preparation of ramipril-containing capsule using talc (10,000)

50 g of ramipril and 1,950 g of talc were mixed with apples using a 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Examples 8 to 9  : Preparation of ramipril-containing capsule using pregelatinized starch

Comparative Example 8  : Commercially available formulations in the United States (10,000)

50 g of ramipril and 1,950 g of pregelatinized starch were mixed with apples using No. 50 sieve. It was filled into No. 3 capsules to obtain a final weight of 250 mg.

Comparative Example 9  : Domestic commercial preparations (Tritace tablets) (10,000)

9 g of hydroxypropylmethyl cellulose (HPMC) was dissolved in 180 g of purified water to prepare a 5% aqueous solution, and then sprayed into 50 g ramipril in a fluidized bed to granulate and dried at 50 ° C. 465.5 g of pregelatinized starch, 470 g of microcrystalline cellulose, 5 g of sodium stearate fumarate, and 0.5 g of ferric oxide were mixed with the dried product. This mixture was tableted directly to a final weight of 100 mg.

Experimental Example 1  : Content change experiment of capsule

The capsules prepared in Example 1 and Comparative Examples 1 to 7 were left to stand at a temperature of 50 ° C. and a relative humidity of 75% for 15 days, and the content of ramipril was observed.

The results are shown in Table 1.

Initial content (%) % After 15 days % Change Example 1 99.5 95.9 3.6 Comparative Example 1 98.1 89.4 8.7 Comparative Example 2 97.3 87.0 10.3 Comparative Example 3 97.9 87.7 10.2 Comparative Example 4 98.2 71.4 26.8 Comparative Example 5 96.6 83.8 12.8 Comparative Example 6 97.5 75.0 22.5 Comparative Example 7 98.5 90.0 8.5

As shown in Table 1, the formulation for oral administration consisting of ramipril and lactose was 3.6% in content change, but the content change of Comparative Examples 1 to 7 consisting of ramipril and other additives was significantly changed to 8.5 to 26.8%.

Experimental Example 2  : Experiment of content change of capsule according to the present invention

The capsules prepared in Examples 1 to 8 were allowed to stand for 5 months at a temperature of 40 ° C. and a relative humidity of 75%, and the content of ramipril was observed.

The results are shown in Table 2.

Initial content (%) Content after 5 months % Change Example 1 [Ramipril (2.5% by weight) + Lactose (97.5% by weight)] 99.5 96.0 3.5 Example 2 [ramipril (2.5% by weight) + lactose (96.5% by weight) + microcrystalline cellulose (1% by weight)] 98.7 93.8 4.9 Example 3 [Ramipril (2.5% by weight) + Lactose (96.5% by weight) + Mannitol (1% by weight)] 97.5 92.4 5.1 Example 4 [Ramipril (2.5% by weight) + Lactose (96.5% by weight) + Corn starch (1% by weight)] 98.1 93.6 4.5 Example 5 [Ramipril (2.5% by weight) + Lactose (96.5% by weight) + Glyceryl bicarbonate (1% by weight)] 98.5 93.2 5.3 Example 6 [Ramipril (2.5% by weight) + Lactose (96.5% by weight) + Sodium lauryl sulfate (1% by weight)] 97.2 92.9 4.3 Example 7 [Ramipril (2.5% by weight) + Lactose (96.5% by weight) + Magnesium Stearate (1% by weight)] 97.9 92.7 5.2 Example 8 Ramipril (2.5 wt%) + Lactose (96.5 wt%) + Talc (1 wt%) 97.3 93.4 3.9 Ramipril (2.5 wt%) + Lactose (95.5 wt%) + Talc (2 wt%) 97.2 92.8 4.4 Ramipril (2.5 wt%) + Lactose (94.5 wt%) + Talc (3 wt%) 97.0 92.1 4.9

As shown in Table 2, the formulation of the present invention consisting of ramipril and lactose had a content change of 3.5%, but the content change of Examples 2-8 using ramipril, lactose and other pharmaceutically acceptable additives was 3.9-5.3. There was a slight change in content in%.

Therefore, it can be seen that the formulation for oral administration containing ramipril according to the present invention is stable at a temperature of 40 ° C. and a relative humidity of 75%.

Experimental Example 3  : Experiment of content change of capsules and existing commercial formulations according to the present invention

The capsules prepared in Example 1 and Comparative Examples 8 to 9 were left to stand for 5 months at a temperature of 40 ° C. and a relative humidity of 75%, and the content of ramipril was observed.

The results are shown in Table 3.

Initial content (%) Content after 5 months % Change Example 1 99.5 96.0 3.5 Comparative Example 8 99.4 93.6 5.8 Comparative Example 9 97.5 92.8 4.7

As shown in Table 3, the formulation of the present invention consisting of ramipril and lactose had a content change of 3.5%, but the content change of Comparative Examples 8-9, which is an existing commercial formulation consisting of ramipril and pregelatinized starch, was 4.7-5.8. There was a slight change in content in%.

Therefore, it can be seen that the formulation for oral administration containing ramipril according to the present invention is superior in stability to commercially available formulations.

The formulation for oral administration of the present invention can maintain excellent stability of ramipril without changing formulation by using only lactose as an excipient without using other additives. In addition, even if less than 5% of the content of lactose by replacing other additives can maintain the stability of ramipril equivalently when only lactose as an excipient. Therefore, the formulation for oral administration according to the present invention is superior in stability to existing commercial formulations, and the manufacturing process is simple and economically useful.

Claims (5)

delete A formulation for oral administration comprising 0.5 to 10% by weight of ramipril, 85 to 99.49% by weight lactose, and 0.01 to 5% by weight of one pharmaceutically acceptable additive selected from the group consisting of talc and sodium lauryl sulfate. The oral preparation of claim 2, wherein the talc is included in an amount of 1-3 wt%. The oral preparation of claim 2 or 3, wherein the preparation is a capsule. 4. The oral preparation of claim 2 or 3, wherein the capsule comprises 2.5-10 mg of ramipril per capsule.