KR20100008419A - Stability increased fast soluble amlodipine tablet and processes for the preparation thereof - Google Patents

Abstract

PURPOSE: A rapidly integrating tablet containing amlodipine with enhanced preservation and a method or manufacturing the same are provided to improve chemical stability. CONSTITUTION: A method for manufacturing a rapidly integrating tablet containing amlodipiine or its pharmaceutically acceptable salt comprises: a step of mixing water-soluble excipient and disintegrating agent of sugar alcohol; a step of stirring the mixture and adding purified water to produce granule; a step of mixing amlodipine or its pharmaceutically acceptable salt; and a step of tabletizing. The water-soluble excipient is erythritol, mannitol, sorbitol, or xylitol.

Description

Stability increased fast soluble Amlodipine tablet and processes for the preparation of the present invention

The present invention relates to a process for the preparation of fast disintegrating tablets containing amlodipine or pharmaceutically acceptable salts, and to a fast soluble tablet prepared thereby.

In the case of oral administration of medicines, tablets, capsules, granules, powders, solutions, and the like are considered.

Liquid formulations are suitable for elderly, severe patients and infants who have difficulty swallowing, but have the disadvantages of poor quantification and physical and chemical stability. It has a drawback that is difficult to take, tablets are suitable for administering the correct dose, and there is a convenience in distribution and storage, but has a problem in that swallowing is difficult in the elderly, severe patients, and infants.

Therefore, as a technique for overcoming the above drawbacks, studies have been made on fast disintegrating tablets which disintegrate rapidly in the oral cavity, which combines the advantages of easy-to-handle tablets with the advantages of easy-to-use tablets. Quick-disintegrating tablets are tablets that are usually dissolved within 15 seconds to 1 minute in the oral cavity, and are suitable formulations for the elderly, severe patients, and the like which are difficult to take tablets.

For example, al. Blood. Scherer (RP Scherer) preparations available on the market Xi display ^® (Zydis ^®) is the trade name from four freeze as sokbung unlocking formulation mouth commercially successful only have the advantage of being rapidly disintegrated in the oral cavity Because it is made by the drying technology has a disadvantage that it is difficult to secure physical stability during the distribution process.

Japanese Patent Application Laid-Open No. 8-291051 proposes a method of compressing the granules consisting of drugs, water-soluble polymers and sugars at low pressure in a tableting machine, and then drying them in a humidified condition. If the main ingredient is a drug that is weak to moisture because of humidification, there is a problem that the physical stability of the drug is lacking.

Korean Patent Laid-Open Publication No. 2001-102122 proposes a method for producing fast disintegrating tablets in the oral cavity by a general wet granulation method using pharmaceutical additives having a fast dissolution rate in water, but this method is also unstable in moisture such as amlodipine. There is a problem in that the application of the drug lacks the storage stability of the product.

Korean Patent Laid-Open Publication No. 2001-6835 proposes a method for manufacturing by a general direct method including crospovidone as a spray-dried mannitol and a co-disintegration, but the method is described in the above techniques. Compared to the slow dissolution in the oral cavity has a disadvantage.

On the other hand, amlodipine is a calcium channel blocker that acts for a long time in the human body, and is useful for treating cardiovascular diseases and hypertension. The chemical formula of amlodipine is 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicar It is a carboxylate, and the structure is shown in following formula (1).

<Formula 1>

In general, high blood pressure disease usually requires a steady dose of anti-hypertensive drugs, and most of the elderly patients after the middle age. Therefore, when developing a fast disintegrating tablet formulation containing amlodipine, it can be expected that the clinical excellence of improving patient compliance with the medication.

Amlodipine is prepared and administered in the form of pharmaceutically acceptable acids and salts because of the disadvantage of not only amorphous but also poor stability of the compound. Currently, it is manufactured and marketed in the form of various salts such as besylate salt, chamlate salt, maleate salt, orotate salt, adipate salt, nicotinate salt.

However, the amlodipine in the salt form also has a problem that is unstable to light and moisture. Therefore, amlodipine products require attention to the physicochemical stability of the formulation during the shelf life. For this reason, attention should be paid to the use of excipients when formulating oral solid preparations containing common amlodipine.

Amlodipine is known to be unstable in lactose, magnesium stearate, and water and lacks chemical stability (Amlodipine besylate-excipients interaction in solid dosage form, Pharm Dev Technol 2004; 9 (1); 15-24). In the manufacturing process containing moisture, such as wet granulation, the chemical stability of the drug is difficult to market as a product.

Therefore, drugs that are unstable to moisture, such as amlodipine or pharmaceutically acceptable salts, lack the stability of the preparation when Sokbung tablets are prepared by the conventional methods of containing water such as lyophilization, humidification drying, and wet granulation. There is a need for a new method for the preparation of fast disintegrating tablets.

To this end, the water-soluble excipient that dissolves quickly in the mouth should be the main composition, there should be no contact between the drug and the water in the manufacturing process, and it should be possible to produce a good quality product by the general tablet manufacturing method. In addition, there should be no breakage or chemical change of the tablet during the shelf life.

The present invention provides a method for preparing fast disintegrating tablets containing amlodipine or a pharmaceutically acceptable salt having ample storage stability within the shelf life despite the physical and chemical properties of amlodipine in water-stable properties, and fast disintegrating tablets prepared therefrom. To provide.

The present invention also provides a fast disintegrating tablet containing amlodipine or a pharmaceutically acceptable salt which shows rapid disintegration and good feeling in the mouth.

Hereinafter, the present invention will be described in detail.

The present invention must satisfy the following conditions in order to achieve the above object.

First, a water-soluble excipient that dissolves quickly in the mouth should be the main composition,

Second, there should be no contact between the drug and moisture in the manufacturing process,

Third, it should be possible to manufacture products of excellent quality even with the general manufacturing method of tablets,

Fourth, there should be no storage breakage or chemical change during the shelf life, so storage stability should be excellent.

In order to achieve the above object, (1) mixing a water-soluble excipient and a disintegrant of sugar alcohols, (2) preparing granules by adding purified water while stirring the mixture of (1), (3) It provides a method for producing the fast disintegrating tablet comprising the step of mixing the amlodipine or a pharmaceutically acceptable salt thereof and the granules prepared in step (2), (4) tableting.

Step (1) in the manufacturing method according to the present invention is a step of mixing a water-soluble excipient and a disintegrant, the water-soluble excipient of sugar alcohols is an important factor in determining the dissolution rate of the amlodipine formulation and storage stability of the formulation.

Step (2) in the production method according to the present invention uses purified water as a solvent for producing the granules, it is possible to make good granules without any additional binder in the water-soluble excipient. In view of the fact that amlodipine, the active ingredient of the present invention, is a material that is unstable in water, the direct-acting fast disintegrating tablet using the direct-acting excipient did not obtain satisfactory results in dissolution rate. In addition, since it is manufactured with purified water instead of an organic solvent, there is no problem of safety and environmental toxicity of the worker during the manufacturing process, and also helps the safety of the patient.

Step (3) in the preparation method adds co-disintegrants, lubricants, sweeteners, flavoring agents, etc. which are used in the manufacture of conventional tablets of amlodipine or a pharmaceutically acceptable salt thereof and granules prepared in step (2). It may include including to mix.

Step (4) in the manufacturing method is preferably tableted using a rotary tableting machine.

The manufacturing method according to the present invention is characterized in that the fast disintegrating granules are prepared with a water-soluble excipient and a disintegrating agent, and then fast disintegrating tablets by post-mixing with a drug.

By the preparation method as described above, the amlodipine or the pharmaceutically acceptable salt thereof as the active ingredient of the present invention can be prevented from the lack of stability through wet granules despite the drug lacking stability in water.

Pharmaceutically acceptable salts of amlodipine in the present invention include various salt forms, such as besylate salt, chamlate salt, malate salt, orotate salt, adipate salt, nicotinate salt and the like.

The water-soluble excipient of the present invention may be selected from sugar alcohols such as erythritol, mannitol, xylitol, sorbitol, maltitol, and preferably erythritol may be selected. Direct excipients generally known to disintegrate quickly, such as Starlac ^® (Roquette), F-MELT ^® (Fuji chemical), spray-dried mannitol (Merck), dextrate (Edward Mendell), direct sugar (Edward) Mendell) and the like are not included in the water-soluble excipient of the present invention because the present invention does not exhibit the desired effect of rapid disintegration.

The disintegrant of the present invention may be selected from one or two or more from disintegrants generally used in the manufacture of tablets, and includes low-substituted hydroxypropyl cellulose, starch and the like.

Since the ratio of the water-soluble excipient and disintegrant may affect tableting disorders during mass production of tablets, in the present invention, the water-soluble excipient and disintegrant may preferably be included in a ratio of 60 to 80:20 to 40, most preferably May be included in a ratio of 70:30.

The fast disintegrating tablet of the present invention may further include co-disintegrants, lubricants, sweeteners, flavoring agents and the like used in the manufacture of conventional tablets.

The fast disintegrating tablet and the preparation method according to the present invention provide the following advantages.

First, by eliminating moisture contact with drugs in the manufacturing process, the chemical stability of the formulation is greatly improved, and the storage stability is very excellent.

Second, because it disintegrates quickly in the oral cavity, it can increase medication compliance to patients with dysphagia, such as elderly, children, or severely ill, and can be administered with confidence even for patients who limit water.

Third, the present invention can be manufactured with the existing rotary tableting technology, unlike the special fastening technology for complex manufacturing special equipment or processes, the process is also simple, it can greatly reduce the production cost.

Fourth, in the production of fast disintegrating granules, because it is made of purified water, not an organic solvent, safety in terms of worker and environmental toxicity during the manufacturing process is secured.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

<Examples 1-3> Preparation of fast disintegrating tablets according to the present invention

Amlodipine orotate fast disintegrating tablets were prepared in the following compositions and contents.

Sugar alcohols (mannitol, sorbitol, erythritol), corn starch, low-substituted hydroxypropyl cellulose (L-HPC) apples into a 40 mesh sieve and mixed. The mixture is combined with purified water as a solvent. The union is assembled into a 30 mesh sieve, and then dried in a 40 degree column dryer. Post-mix the drug to the prepared fast disintegrating granules. About 111 mg of fast disintegrating tablets were prepared by mixing crospovidone, a flavoring agent, a sweetening agent, and a lubricant with a co-disintegrating agent, followed by tableting with a single tablet press.

< Comparative example  1-5> For direct hits  With excipients Direct stroke Fast disintegration  Manufacture of tablets

Amlodipine orotate fast disintegrating tablets were prepared in the following compositions and contents.

The active ingredient amlodipine orotate and the excipient for direct hitting are mixed with apples in a 40 mesh sieve. Crospovidone is mixed as a co-disintegrant and then flavored, sweetened and glidant mixed. The resulting mixture was compressed into a single tablet press to prepare about 107 mg of fast disintegrating tablets. The hardness of the tablets was compressed to 5 KP in consideration of the physical stability of the drug during distribution.

<Comparative Examples 6-9> Preparation of quick disintegrating tablet by wet granulation method using sugar alcohol

1) Preparation of fast disintegrating tablet using 1% starch gelatin solution as binding solution

A portion of corn starch (0.65 mg / tablet) among the components described in Comparative Example 6 in Table 3 was taken, dispersed in purified water, and warmed to obtain a 1% starch gelatinization solution. Amlodipine orotate, sugar alcohols mannitol, corn starch (0.65mg per sugar mixed with the remainder as a powder), low-substituted hydroxypropyl cellulose (L-HPC) in a 40 mesh sieve apples and mixed. The mixture is combined with 1% starch gelatinization solution as binding solution. The union is assembled into a 30 mesh sieve, and then dried in a 40 degree column dryer. After the dried product was established in a 35 mesh sieve, crospovidone, a flavoring agent, a sweetening agent, and a lubricant were mixed as co-disintegrating agents, and then tableted with a single tablet press to prepare 111 mg of fast disintegrating tablets. . In consideration of physical stability during distribution of the drug, the hardness of the tablets was compressed to 5 KP.

2) Preparation of fast disintegrating tablets using purified water as a binder

Among the components described in Comparative Examples 7 to 9 of Table 3, amlodipine orotate, sugar alcohols (mannitol, sorbitol, erythritol), corn starch and low-substituted hydroxypropyl cellulose (L-HPC) were apples with 40 mesh bodies. Then mix. The mixture is combined with purified water into a solvent. The union is assembled into a 30 mesh sieve, and then dried in a 40 degree column dryer. After the dried product was established in a 35 mesh sieve, crospovidone, a flavoring agent, a sweetening agent, and a lubricant were mixed as co-disintegrating agents, and then tableted with a single tablet press to prepare about 111 mg of fast disintegrating tablets, respectively. To 9; The hardness of the tablets was compressed to 5 KP in consideration of the physical stability of the drug during distribution.

Experimental Example 1 Dissolution rate evaluation

Intraoral fasting tablets of amlodipine orotate prepared in Examples 1 to 3 and Comparative Examples 1 to 9 according to the present invention were administered to 20 healthy males and females, and the dissolution rate of each formulation was evaluated. Dissolution rate evaluation was carried out in the following five steps. The test results are shown in Table 4 below.

Fast: 10-20 seconds

2. Satisfied: 20-30 seconds

3. Normal: 30 ~ 45 seconds

4. Not satisfied: 45 ~ 60 seconds

5. Slow: more than 60 seconds

As a result of the evaluation, when preparing the fast disintegrating tablet using the excipients for direct hitting as in Comparative Examples 1 to 5, it did not have a satisfactory oral dissolution rate. When granules were prepared using sugar alcohols having excellent oral dissolution rates, they showed good dissolution rates. Meanwhile, among sugar alcohols, erythritol used in Comparative Examples 9 and 3 was found to be the best in terms of solubility.

Therefore, in the present invention, it can be seen that the water-soluble excipient of sugar alcohols is an important factor in determining the dissolution rate of the amlodipine formulation.

Experimental Example 2 Accelerated Stability Evaluation of Fast Disintegrating Tablets

The storage stability of the fast disintegrating tablets prepared in Examples 1 to 3 and the fast disintegrating tablets prepared in Comparative Examples was evaluated. As a control agent, a commercially available amlodipine orotate preparation (orodipine tablet, Dong-A Pharmaceutical) was used. Properties, hardness, while keeping the test formulation under accelerated conditions (40 degrees 75% RH) for 6 months. The soft substances, the contents and the degradation products of the main components, were evaluated. The content (%) was expressed as a relative value with the initial content as 100%. Content and analog were analyzed using the following HPLC system. The evaluation results are shown in Table 5 below.

<Content liquid chromatograph condition>

Detector: UV absorbance photometer (wavelength 237 nm)

Mobile phase: Methanol: 0.03 M potassium dihydrogen phosphate solution (600: 400, v / v)

Column temperature: room temperature

Flow rate: 1.5 mL / min

<Flexible liquid chromatograph conditions>

Detector: UV absorbance photometer (wavelength 237 nm)

Column: A column packed with a 5 µm octadecylsilylated silica gel for a liquid chromatograph in a stainless tube having a diameter of 3.9 mm and a length of 15 cm.

Column temperature: room temperature

Mobile phase: Acetonitrile, methanol, water (7 mL of triethylamine was added to 1 L of water and the pH was adjusted to 3.0 ± 0.1 with a phosphate solution) Mixed solution 15: 35: 50 (v / v / v)

Flow rate: 1.0 mL / min

Area measurement range: about 3 times the amlodipine holding time

1) Appraisal

In Comparative Example 1, since the active ingredient amlodipine is a material that is unstable in water, the rapid disintegrating tablet using direct excipient or rapid storage disintegration appeared in the accelerated storage conditions. Therefore, the storage stability of the product within the shelf life was suspected.

By the way, it can be seen that the fast disintegrating tablets prepared in Examples 1 to 3 and the fast disintegrating tablets prepared in Comparative Examples 6 to 9 were prepared by mixing water-soluble excipients of sugar alcohols, which did not cause a change in properties. have.

Therefore, in the present invention, it can be seen that the water-soluble excipient of sugar alcohols is an important factor in the storage stability of amlodipine fast disintegrating preparations.

2) content change and evaluation of lead substances

As a result of the content change evaluation for 6 months of storage under accelerated conditions, the fast disintegrating tablets prepared in Examples 1 to 3 according to the present invention showed less than 1% of content change compared to the initial content, showing excellent storage stability, while comparing with Comparative Example 1 and Examples 6 to 9 showed about 3% change in content relative to the initial content.

In addition, in general, the flexible material of commercially available amlodipine formulation is the flexible material D and Unknown flexible material of 0.3% or less, the fast disintegrating tablet prepared in Examples 1 to 3 according to the present invention hardly produced a flexible material In addition, there was no change compared to the initial flexible material, indicating that the storage stability was greatly improved, and the storage stability was equal to or higher than that of the control formulation (orodipine tablet commercially available).

On the contrary, in Comparative Example 1, since the active ingredient amlodipine is a material that is unstable in water, it can be seen that a rapid disintegrating tablet using a direct-acting excipient or a softening material was generated, which is a amine of starlac and amlodipine. The group is believed to cause the Maillard reaction (Amlodipine besylate-excipients interaction in solid dosage form, Pharm Dev Technol 2004; 9 (1); 15-24).

In Comparative Example 6, a fast disintegrating tablet was prepared by using a 1% starch gelatinized solution as a binding solution, and Comparative Examples 7 to 9 were fast disintegrating tablets prepared by wet granulation using sugar alcohols, which lacked stability in moisture. Wet granules, including the drug amlodipine, seem to lack stability.

3) results

Therefore, amlodipine, which is an active ingredient of the present invention, has sufficient storage stability within the shelf life by a method of preparing a fast disintegrating granule by mixing a water-soluble insulator and a disintegrating agent, and then mixing the drug amlodipine after the preparation. Eggplant can be seen that it can prepare amlodipine fast disintegrating tablets.

Experimental Example 3 Evaluation of Tablet Tableting Disorder Improvement in Mass Production

In order to improve the sticking phenomenon of the tablet surface which may occur when the tablet press is rotated using a rotary tableting machine, the composition of Example 3 according to the present invention is changed in the ratio of corn starch and erythritol used in the preparation of fast disintegrating granules as shown in Table 6 below. We evaluated the tableting disorder and dissolution rate.

As a result, when the ratio of erythritol and starch is 70/30, tableting disorder does not occur and dissolution rate is also excellent. By preparing the granules with the same composition as in Example 3-4 and post-mixing the drug in a mass production amount of 100,000 tablets, it was possible to prepare a fast disintegrating tablet in oral cavity of excellent quality. In addition, this method can be produced as a commercially available rotary tablet press without the need for a separate facility, and the process is simple and commercially useful.

Experimental Example 4 Comparative Evaluation of Solubility of Mass Production Formulations

The solubility was compared with the amlodipine formulations (orodipine tablets, Dong-A Pharm. Co., Ltd.) commercially available with ammodipine orotate orally disintegrating tablets produced in large quantities in Example 3-4. The evaluation method was placed one tablet and orodipine tablet in the oral cavity of the present invention on a 30 mesh sieve, and measured the time (through the sieve) the tablet disappears with artificial saliva and is shown in FIG. The composition of artificial saliva is as follows. KH ₂ PO ₄ 12 Mm, NaCl 40 mM, CaCl 2 1.5 mM, NaOH (Adjust pH 6.2)

As shown in FIG. 1, the fast disintegrating tablet in the oral cavity disappeared after 20 seconds as compared to the general amlodipine formulation to maintain its form.

Experimental Example 5 Pharmacokinetic Evaluation

Pharmacokinetic comparative evaluation was carried out on the fast disintegrating tablet prepared in the composition of Example 3-4 and the commercial product Orodipine ^® tablet. Elution test of 500 mL of pH 1.2 solution, pH 4.0 solution, pH 6.8 solution and water similar to the physiological conditions in the human body was performed at 50 rpm using the Paddle method and the results are shown in FIGS. 2 to 5.

As can be seen in Figures 2 to 5, the dissolution rate between the orally disintegrating tablet in the oral cavity of the present invention and the orodipine tablet containing amlodipine orotate salt is similar, the orally disintegrating tablet in the oral cavity of the present invention and orodipine Tablets can be expected to be equivalent in terms of pharmacokinetics and efficacy.

FIG. 1 shows the results of measuring the time when tablets disappear (pass through a sieve) by placing one fast-release tablet in Example 3-4 according to the present invention and one commercially available orodipine tablet on a 30 mesh sieve. .

Figure 2 shows the results of comparative dissolution test in pH 1.2 solution of Sorb disintegrating tablet of Example 3-4 according to the present invention and orodipine tablet which is a commercial preparation.

Figure 3 shows the results of the comparative dissolution test in pH 4.0 solution of the fast disintegrating tablet of Example 3-4 according to the present invention and orodipine tablets commercially available.

Figure 4 shows the results of comparative dissolution test in pH 6.8 of the fast disintegrating tablet of Example 3-4 according to the present invention and orodipine tablet which is a commercial preparation.

Figure 5 shows the results of the comparative dissolution test in the water of the fast disintegrating tablet of Example 3-4 according to the present invention and orodipine tablets commercially available.

Claims (8)

(1) mixing a water-soluble excipient of a sugar alcohol and a disintegrant; (2) preparing granules by adding purified water while stirring the mixture of step (1); (3) mixing amlodipine or a pharmaceutically acceptable salt thereof with the granules prepared in step (2); And (4) tableting step Method for producing a fast disintegrating tablet containing amlodipine or a pharmaceutically acceptable salt thereof characterized in that it comprises a. The method of claim 1, wherein the water-soluble excipient of sugar alcohols is selected from the group consisting of erythritol, mannitol, sorbitol, lactyrol or xylitol, and a method for producing a fast disintegrating tablet of amlodipine or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the disintegrant is selected from the group consisting of starch, low-substituted hydroxypropyl cellulose, or a fast disintegrating tablet of amlodipine or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the water-soluble excipients and disintegrants of sugar alcohols are contained in a ratio of 60 to 80:20 to 40 in a ratio of ammodipine or a pharmaceutically acceptable salt thereof. The method of claim 4, wherein the water-soluble excipient and the disintegrant are included in a ratio of 70:30. 2. The fast disintegrating amlodipine or its pharmaceutically acceptable salts according to claim 1, further comprising a co-disintegrant, a lubricant, a sweetener, and a flavoring agent, which are used in the conventional tablet preparation in step (3). Process for preparing degradable tablets. The method of claim 1, wherein step (4) is a method for producing a fast disintegrating tablet of amlodipine or a pharmaceutically acceptable salt thereof, which is compressed using a rotary tablet press. A fast disintegrating tablet containing amlodipine or a pharmaceutically acceptable salt thereof prepared by any one of claims 1 to 7.

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