KR0173739B1 - Sustained Release Pharmaceutical Compositions - Google Patents

Abstract

The present invention relates to oral sustained release compositions of acyclovir. By using carboxymethyl cellulose sodium and hydroxypropyl methyl cellulose in a weight ratio of 1: 1 to 1: 2 as a matrix base, acyclovir is eluted at a constant rate for at least 12 hours, thereby showing a sufficient therapeutic effect by taking 1 to 2 times per day.

Description

Sustained Release Pharmaceutical Compositions

The present invention relates to an oral composition in which acyclovir is useful as an antiviral agent. More specifically, the present invention provides sufficient therapeutic effect by taking 1-2 cycles a day by eluting acyclovir at a constant rate for a long time. It relates to an oral sustained release composition.

Acyclovir is an antiviral agent that specifically inhibits the herpes virus.It is a topical disease such as keratitis caused by herpes simplex virus, recurrent and recurrent genital herpes and herpes labialis, as well as children with chickenpox and immunodeficiency. It has been usefully used for the treatment of systemic diseases such as viral infections.

In order to treat systemic diseases, acyclovir is taken orally or by injection.

However, when acyclovir is rapidly absorbed into the body, kidney damage, hematuria, and creatinine levels are increased. Oral administration is mainly absorbed in the upper part of the small intestine. There is a disadvantage that the rest is excreted as it is.

Therefore, injections have a disadvantage of rapidly increasing the concentration of acyclovir in the blood immediately after administration, kidney damage, hematuria, and creatinine levels. There is also a hassle to be administered 4 to 5 or more times a day.

Acyclovir oral preparations include Daewon acyclovir tablets (Daewon Pharmaceutical Co., Ltd.), Bylax tablets (Koryo Pharmaceuticals), Barcrobi tablets (Hanpok Pharmaceuticals), Ecrobar tablets (Kyungdong Pharmaceuticals), and Zovirax tablets (Dong-A Pharmaceuticals). This progresses rapidly and most of the elution is achieved within 30 minutes-1 hour, after which the dissolution rapidly decreases. Therefore, only about one third of the dose is absorbed and the rest is excreted in order to exhibit a sufficient therapeutic effect has to be taken at least four to five times a day.

As described above, since the conventional techniques are cumbersome to take 4 to 5 or more times a day in order to have a sufficient effect, acyclovir is eluted in a constant amount for a long time so that the drug is continuously supplied at a constant rate in small amounts. Therefore, the development of oral sustained-release preparations that can provide sufficient therapeutic effect by taking acyclovir once or twice a day is urgently needed.

Jin-Ho Cho prepared suspensions with microcapsules in order to continuously elute acyclovir (Master's Thesis, Chung-Ang University, 1993).

However, the prior art has extended the elution time than conventional products, the blood concentration of acyclovir does not remain constant after administration, and after reaching the maximum concentration 90 minutes after the administration, the blood concentration rapidly decreases and the therapeutic effect is rapidly increased. When the average residence time in the body is 175 minutes and 3-4 hours after administration, the blood concentration of acyclovir drops below the effective concentration, and the disadvantage of having to take 4-5 or more times a day to obtain the desired therapeutic effect is eliminated. I can't. In addition, according to the coacervation principle, a mixture of carbopol and gelatin is converted into coacervate at pH 3.3-3.5 to obtain a microcapsule suspension. There is a disadvantage to maintain.

Therefore, the present inventors have tried to develop a sustained-release formulation for oral release that has a sufficient therapeutic effect by taking 1 to 2 times a day to find a pharmaceutical additive that continuously maintains the elution of acyclovir at a constant rate and an appropriate amount for more than 12 hours. Was done.

In general, a sustained-release preparation in which a drug slowly elutes is used as a matrix preparation in which the main drug is dispersed in a matrix in which a preparation aid such as a hydrophilic polymer forms a continuous phase. These hydrophilic polymers swell by digestive fluid in the stomach to form a gel, so that the medicine is slowly eluted while staying in the stomach for a long time.

Such hydrophilic polymers include cellulose derivatives such as methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and carboxymethylcellulose sodium (Na-carboxymethylcellulose, Na-CMC). And natural polymers include tragacanth, xanthan gum, arabian gum, and the like, and carbomers and eudragit as synthetic polymers.

The dissolution rate of the drug is affected by the viscosity of the hydrophilic polymer, the content ratio of the drug of the hydrophilic polymer, the tableting pressure, the shape and thickness of the tablet, the excipient, the particle size of the drug, and the surface area of the tablet. It is determined by the viscosity and the content ratio of the hydrophilic polymer and the medicine, and the physical and chemical properties of the medicine.

Shah, A. prepared ibuprofen, diclofenac, indomethacin, etc. as a sustained release formulation using HPMC, MC, Na-CMC and the like (European Patent Publication EP227814), Sheth P.R. Et al. Prepared acetylsalicylic acid as a sustained release formulation using HPMC, HPC and the like (US Pat. No. 4,126,672).

In addition, Devi et al. Prepared a matrix-type tablet by mixing HPMC and Na-CMC in Oxoprenolol in a weight ratio of 1: 0.4: 1.6 to prepare a sustained-release formulation for oxoprenolol. Pharm.Res., 6 (4), p313-317, Apr. 1989)

However, the same ingredients or compositional ratios as above can not provide sufficient therapeutic effect by taking acyclovir once or twice a day. Therefore, the present inventors have sufficient therapeutic effect by taking 1-2 cycles a day by eluting acyclovir at a constant rate for more than 12 hours. As a result of many studies to find a hydrophilic polymer system to show the result that the composition containing Na-CMC and HPMC as a matrix base eluted acyclovir at a constant rate for more than 12 hours to complete the present invention.

Accordingly, the present invention provides an oral sustained release composition having a new composition exhibiting a sufficient therapeutic effect by taking 1 to 2 times a day by eluting acyclovir at a constant rate for a long time, unlike in the prior art, in preparing acyclovir oral preparation. Its purpose is to.

Hereinafter, the present invention will be described in detail.

The present invention provides an acyclovir oral composition comprising acyclovir as an active ingredient,

It is characterized by containing carboxymethyl cellulose sodium (Na-CMC) and hydroxypropyl methyl cellulose (HPMC) as a matrix base.

Referring to the present invention in more detail as follows.

Na-CMC and HPMC are used as matrix bases in the preparation of the acyclovir oral dosage composition provided by the present invention, and the composition of HPMC to Na-CMC is preferably 1: 1 to 1: 2 by weight.

If the ratio of HPMC to Na-CM is more than 1: 2 weight ratio, the viscosity of the polymer mixture is increased, so that the dissolution rate of the main medicine through the swollen gel layer is not sufficient, so that the dissolution is not sufficient, and the treatment is not sufficiently performed. When the viscosity of the polymer mixture decreases, the gel layer, which is a drug release mechanism, is rapidly eroded by the digestive fluid, so that the sustained-release function of the formulation is degraded or the gel disappears quickly.

It is preferable that Na-CMC and HPMC of the said composition be 5-20 weight ratio in a unit formulation.

If the content of Na-CMC and HPMC is 20 weight ratio or more, the diffusion of the drug through the polymer gel layer is lowered, so that the dissolution rate is not sufficient, and the elution is not sufficient. It becomes difficult, and if it is 5 weight ratio or less, the elution rate is too fast and it cannot hold | maintain elution more than 12 hours.

The composition ratio of acyclovir to Na-CMC and HPMC is preferably 1: 2.5 to 4.5 by weight.

If the ratio of acyclovir to Na-CMC and HPMC is less than 1: 2.5 by weight, the elution rate of the acyclovir is too low. If the ratio is greater than 1: 4.5, the elution rate is accelerated and completed before 12 hours, making it difficult to expect the sustainability of the drug.

Acyclovir is preferably contained 100-500 mg per unit formulation, particularly preferably 200-300 mg.

If more than 500mg of acyclovir per unit is contained, the initial elution is excessively absorbed, and the amount that passes through the absorption site is increased so that the bioavailability decreases. If the content is less than 100mg, sufficient amount is not eluted to obtain sufficient therapeutic effect. Hard.

Oral sustained release formulations of the present invention may include, in addition to Na-CMC and HPMC, pharmaceutically acceptable conventional excipients that do not affect the elution of acyclovir.

Since the oral sustained release formulation of the present invention continuously elutes acyclovir, the concentration of acyclovir in blood is kept constant for at least 12 hours, so a sufficient therapeutic effect can be obtained by taking 1-2 times daily.

In addition, the sustained-release preparation of the present invention and sodium starch glycolate, croscarmellose sodium, cross-linked, and the rapid disintegrating agent of the present invention in order to ensure that the acyclovir is eluted at a concentration showing a sufficient therapeutic effect immediately after taking it. It may be formulated into a two-layer tablet and a fast-release portion having a fast-release function containing one or more components selected from poly-vinylpyrrolidone (cross-linked polyvinylpyrrolidone) as an excipient. The immediate release having such rapid release function immediately elutes the acyclovir at a concentration that shows a sufficient therapeutic effect so that the immediate release has a therapeutic effect.

It is preferable to contain these rapid disintegrating agents so that it may be 15-25 weight ratio of the total amount of a rapid release part, and it is preferable to make a ratio of acyclovir and a rapid disintegrating agent be 1: 2-1: 4 weight ratio.

At this time, if the content of sodium starch glycolate, croscarmellose sodium, and cross-linked polyvinyl pyrrolidone is 25 weight ratio or more, the physical stability such as hardness of the formulation is lowered, and if it is 15 weight ratio or less, rapid dissolution of the formulation becomes difficult. .

The immediate release may include, in addition to sodium starch glycolate, croscarmellose sodium, and cross-linked polyvinyl pyrrolidone, pharmaceutically acceptable conventional excipients that do not affect the elution of acyclovir.

As described above, the present invention dissolves acyclovir at a constant rate for a long time by using Na-CMC and HPMC as a matrix base, and thus, a sufficient therapeutic effect is obtained by taking 1 to 2 times daily. The conventional problem of taking five or more times has been solved.

Hereinafter, the present invention will be described in more detail with reference to examples and examples, but the present invention is not limited by these reference examples and examples.

Reference Example 1

[Production of Dissolution Test Sample for Selecting Matrix Base]

Samples were prepared by the following method to find a component that can be used for the continuous elution of acyclovir among various hydrophilic polymers.

Dissolve 25 mg of Polyvinylpyrrolidine K-30 (PVPK-30) in 2 ml of purified water and use it as a binding solution. Acyclovir, excipients, and each matrix base are homogeneously mixed in the composition of Table 1 and associated with a previously prepared binder. The association is granulated to 20mesh sieves, and the granules are dried in a blow dryer at 50 6 2 ° C to reduce the drying loss to within 2%. The dried product is sieved to 20mesh, and then mixed again with 2mg of Magnesium Stearate (S-Mg). Finally, the mixture is compressed into round tablets having a diameter of 9.65 mm, a thickness of 4.0 mm and a hardness of 7 ± 1 KP to prepare a tablet.

Reference Example 2

[Dissolution Test Results for Selecting Matrix Mechanisms]

The sample prepared in Reference Example 1 was dissolved in 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous sodium dihydrogen phosphate to make 1 liter, and then used as an eluent while maintaining 900 milliliters of pH6.8 buffer at 37 ° C. In the general test method of the Korean Pharmacopoeia, 3 ml of eluate was collected every 1, 3, 6, 9 and 12 hours after the test was rotated at a speed of 100 rpm by the dissolution test method, the first method of dissolution test method, 0.45. After filtration through a membrane having a pore size of micrometer, the filtrate was distilled 10 times with eluent, and the absorbance of acyclovir was measured at wavelength 287 nanometer of the ultraviolet absorbance photometer. Shown in

As shown in Table 2, the components previously used as matrix bases were not suitable as matrix bases for the preparation of sustained release formulations of acyclovirs because of the rapid or eluting acyclovir. E) showed the closest elution effect, but after 12 hours, only about 65% of the acyclovir was eluted to reach a sufficient therapeutic effect, and 35% of the acyclovir, which had not yet been eluted, would not be used. It was expected. Thus, the need to find a new matrix base to elute acyclovir in an appropriate amount for 12 hours has not been addressed.

Reference Example 3

[Dissolution Test for Selecting Matrix Base Composition]

As shown in the results of Table 2 of Reference Example 2, since the existing matrix base alone component is not suitable as a sustained release carrier of acyclovir, it is intended to find a matrix base of a new composition that elutes acyclovir at an appropriate rate for more than 12 hours. MC, HPC-L, HPC-M, HPC-H, and Na-CMC, which easily released acyclovir, were compared with HPMC to increase the elution of HPMC, which showed the best results in the results shown in Table 2 of Reference Example 2. It was prepared in the same manner as in Reference Example 1 by mixing with the composition of Table 3, the dissolution test in the same manner as in Reference Example 2 and the results are shown in Table 4.

As shown in Table 4, when a mixture of HPMC and MC, HPC-L, HPC-M HPC-H, and Na-CMC was used as the matrix base, acyclovir at a constant rate of 12 hours or more only when HPMC and Na-CMC were mixed. It can be seen that it elutes.

Reference Example 4

[Dissolution Test for Determination of Composition Ratio of HPMC and Na-CMC]

Among the results of the experimental results of Reference Example 3, HPMC and Na-CMC mixtures eluting acyclovir at a constant rate for more than 12 hours can be used in the compositions shown in Table 5 below to find the composition ratios that can be used for the continuous elution formulation of acyclovir. Prepared in the same manner as in the dissolution test in the same manner as in Reference Example 2 and the results are shown in Table 6.

As shown in Table 6, it can be seen that the composition of Na-CMC and HPMC elutes acyclovir at a constant rate in a composition ratio of 1: 1: 1: 2 weight ratio.

In the 1: 3 weight ratio of Na-CMC and HPMC, acyclovir was not sufficiently eluted. In the 2: 1 weight ratio, the elution was too fast. If the composition of HPMC to Na-CMC is too high, the viscosity of the swollen gel layer to control the dissolution rate becomes high, the elution of acyclovir is too inhibited, and if the composition of Na-CMC is higher than HPMC, the viscosity of the gel layer to control the diffusion of the drug It is thought that is due to the excessive drop of to accelerate the elution rate of acyclovir.

Reference Example 5

[Experiment of Acyclovir Elution Effect According to Content of Mixed Matrix Base of Na-CMC and HPMC]

Among the results shown in the experimental results of Reference Example 4 in a 1: 1 weight ratio composition of Na-CMC and HPMC eluting acyclovir at a constant rate for more than 12 hours in order to find the dissolution effect according to the content of the matrix base to the composition of Table 7 Prepared in the same manner as in Reference Example 1, the dissolution test in the same manner as in Reference Example 2 and the results are shown in Table 8.

As a result of the above experiment, the content of Na-CMC and HPMC mixed matrix base in the unit formulation was found to be preferably 5 to 20 weight ratio.

Example 1

(1) prescription

200 g of acyclovir

Hydroxypropylmethylcellulose (4,000cps) 36g

Carboxymethylcellulose Sodium 24g

163 g lactose

PolyvinylpyrrolidoneK-30 25g

2 g magnesium stearate

450 g / 1,000 tablets

(2) manufacturing method

① Preparation of binding solution (1,000 tablets)

25 g of polyvinylpyrrolidone K-30 (PVPK-30) is dissolved in 125 ml of purified water, homogenized, and used as a binder.

② Preparation of granules (1,000 tablets)

200 g of acyclovir, 36 kg of hydroxypropyl methyl cellulose (4,000 cps), 24 g of sodium carboxymethyl cellulose and 163 g of lactose are homogeneously mixed in a pony mixer, and then added by the binding solution prepared in (2) -①. This association is granulated in Alexander Granulator using No. 18. The granules thus obtained are dried in a blow dryer at 50 ° C ± 1 so that the drying loss of the granules is 2% or less. The dried material is passed through body No. 18 of the oscillator and established.

③ enactment

2 g of magnesium stearate (S-Mg) was added to the sieved material obtained above, mixed homogeneously, and then tableted into a circular tablet having a diameter of 9.65 mm, a thickness of 4.0 mm, and a hardness of 7 ± 1 KP to prepare a tablet.

Example 2

(1) prescription

200 g of acyclovir

Hydroxypropylmethylcellulose (4,000cps) 48g

Carboxymethylcellulose Sodium 24g

151 g lactose

PolyvinylpyrrolidoneK-30 25g

2 g magnesium stearate

450 g / 1,000 tablets

(2) manufacturing method

① Preparation of binding solution (1,000 tablets)

25 g of polyvinylpyrrolidone K-30 (PVPK-30) is dissolved in 125 ml of purified water, homogenized, and used as a binder.

② Preparation of granules (1,000 tablets)

Granules were prepared according to the method of Example 1 with 200 g of acyclovir, 48 g of hydroxypropylmethylcellulose (4,000 cps), 24 g of sodium carboxymethylcellulose and 151 g of lactose.

③ enactment

2 g of magnesium stearate (S-Mg) was added to the formulation obtained above, mixed homogeneously, and then tableted into a circular tablet having a diameter of 9.65 mm, a thickness of 4.0 mm, and a hardness of 7 ± 1 KP to prepare a tablet.

Example 3

(1) prescription

① Prescription 1 (speed release)

50 g of acyclovir

Lactose 80g

Polyvinylpyrrolidone K-30 10g

Potassium Polyacrylate IRP-88 8g

2 g magnesium stearate

150 g / 1,000 tablets

② Prescription 2 (West Release)

200 g of acyclovir

Hydroxypropylmethylcellulose (4,000cps) 24g

Carboxymethylcellulose Sodium 24g

175 g lactose

PolyvinylpyrrolidoneK-30 25g

2 g magnesium stearate

450 g / 1,000 tablets

(2) Manufacturing Method (Prescription 1: Rapid Release)

① Preparation of binding solution (1,000 tablets)

10 g of polyvinylpyrrolidone K-30 (PVPK-30) is dissolved in 50 ml of purified water, homogenized, and used as a binding solution.

② Preparation of granules (1,000 tablets)

Granules were prepared by the method of Example 1 using 50 g of acyclovir and 80 g of lactose, and then 2 g of magnesium stearate (S-Mg) and 8 g of potassium chlorate IRP-88 were added and mixed homogeneously.

(3) Manufacturing method (prescription 2: slow release part)

① Preparation of binding solution (1,000 tablets)

25 g of polyvinylpyrrolidone K-30 (PVPK-30) is dissolved in 125 ml of purified water, homogenized, and used as a binder.

② Preparation of granules (1,000 tablets)

200 g of acyclovir, 24 g of hydroxypropyl methyl cellulose (4,000 cps), 24 g of carboxymethyl cellulose, and 175 g of lactose were prepared to prepare granules according to the method of Example 1, followed by 2 g of magnesium stearate (S-Mg). .

(4) enactment

After the first tableting using the tableting mixture prepared in Formulation 1, the granules prepared in Formulation 2 are filled into a tableting machine, followed by secondary tableting to prepare a double-layer tablet.

Experimental Example 1

Dissolution Test

The tablet prepared in Example was subjected to the dissolution test in the method of Reference Example 2 and the results are shown in Table 9.

As a result of the dissolution test, it can be seen that the tablet composed of the rapid release portion and the sustained release portion of the present invention elutes the acyclovir at a constant rate for 12 hours or more. Therefore, when taking the tablet of the present invention it can be seen that a sufficient therapeutic effect can be obtained by taking 1-2 times a day.

Claims (7)

A composition containing acyclovir as an active ingredient, wherein the carboxymethylcellulose sodium and hydroxypropylmethylcellulose are contained in a weight ratio of 1: 1 to 1: 2 by weight as a matrix base. The acyclovir oral sustained release composition according to claim 1, wherein the composition ratio of acyclovir to sodium carboxymethylcellulose and hydroxypropylmethylcellulose is 1: 2.5 to 4.5 by weight. The oral sustained release composition of claim 1, wherein the formulation is a tablet. 4. The oral sustained release composition for acyclovir according to claim 3, which contains 5 to 20% by weight of sodium carboxymethylcellulose and hydroxypropylmethylcellulose per unit dosage form. The acyclovir sustained release oral composition according to claim 3, which contains 100 to 500 mg of acyclovir per unit dosage form. The method of claim 3, characterized in that as a rapid disintegrant, sodium starch glycolate, croscarmellose sodium, and cross-link also contain 15-25 weight ratios of at least one component selected from polyvinyl pyrrolidone. Acyclovir oral sustained release composition, characterized in that consisting of a rapid release and two-layer tablet. 7. An oral sustained release composition for acyclovir according to claim 6, wherein 20 to 100 mg of acyclovir is contained in the immediate release portion.