KR100216624B1 - Orally administrable slow-releasing preparations - Google Patents

Abstract

The present invention relates to a sustained release agent wp. More specifically, the present invention relates to oral sustained release preparations formulated using monoglycerides as new sustained release carriers. Sustained release carriers in the sustained-release preparation according to the present invention include glyceryl monooleate, glyceryl monostearate, glyceryl monopalmitate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate and the like. Monoglycerides can be used.

Description

Sustained-release preparations for oral administration

The present invention relates to a novel sustained release formulation for oral administration. More specifically, the present invention is formulated into a sustained release solid preparation for oral administration using a new sustained release carrier to reduce the number of doses to increase medication compliance, and to maintain a constant blood concentration pharmaceutically more useful It is characterized by providing a new formulation.

The present invention can be applied to any active ingredient suitable for use in a sustained release formulation, but is preferably applied to the treatment of hypertension and other cardiovascular agents. In addition to these active ingredients, nonsteroidal anti-inflammatory agents, asthma treatments, sedatives, antibiotics, antispasmodics, expectorants, steroids, and the like can be formulated into sustained release preparations in accordance with the present invention. Particularly representatively, the active ingredient suitable for the preparation according to the present invention is 1,4-dihydropyridine useful as a therapeutic agent for hypertension and cardiovascular system so as to be pharmaceutically preferred in consideration of the quantitative ratio with sustained release carrier and other pharmaceutical additives. As the derivative nifedipine, an active ingredient having a maximum dosage of 200 mg or less is suitable.

Nifedipine is a formulation that is typically formulated as immediate-release soft capsules and taken three or more times a day. However, circulatory drugs, such as nifedipine, generally have to be taken continuously for a long time, so it is just as important to simplify the method of administration. Therefore, in recent years, many studies have been conducted on formulations formulated with sustained-release preparations such that nifedipine can be maintained at a therapeutically effective blood level for more than 24 hours even with only one daily administration.

As a result of these studies, sustained-release preparations and osmotic release modifiers prepared using high molecular materials have been proposed as sustained-release preparations of nifedipine.

For example, hydroxypropylmethylcellulose matrix is disclosed in JPA-06-001716 (1994.1.11), and hydroxypropylcellulose and hydroxypropyl in EP521310A ₂ (1993.1.7). Methyl cellulose solid dispersant, JPA-62-077335 (April 9, 1987), a gel-forming agent using carboxyvinyl polymer, JPA-03-169814 (1991.7.23), hydroxypropyl cellulose, hydroxypropyl methyl Water-soluble polymers such as cellulose, polyvinylpyrrolidone, merylcellulose, etc., and water-insoluble polymers such as microcrystalline cellulose were used in combination. In USP4792452 (December 20, 1988), pH-dependent polymers such as alginic acid and hydroxypropylcellulose, hydroxy PH independent polymers such as propyl methyl cellulose and methyl cellulose were used in combination, and polyvinyl phytolidones were used in EP274176B1 (1992.5.27). W is a sustained release formulation are known obtained.

In addition, many patents using water-insoluble polymer coatings are well known, and they use methods generally used in the pharmaceutical field.

In order for sustained-release preparations to maintain a constant effective blood concentration for up to 24 hours in vivo, the in vitro dissolution pattern exhibits a zero order release pattern, which requires constant release and absorption in the digestive tract. However, in the sustained-release preparation using the water-soluble polymer matrix as described above, since the water-soluble polymer matrix reacts with the water-soluble medium in the digestive tract to form a film of a gel layer on the outer outer portion of the preparation, the release mode is in accordance with the law of diffusion through the membrane. There is a problem that it is difficult to maintain a constant blood concentration continuously for 24 hours in vivo do not show a pattern.

Therefore, in order to improve this, USP4765989, USP5208037, USP5019397, etc., developed a pressure release control agent, and the osmotic release control agent (trade name: Adalat sustained release 30/6) was produced by the osmotic pressure in the tablet. By using the micropore of the correct size and uniformly exhibited the O pattern emission pattern in the digestive tract, uniform emission over a long time was possible. However, the osmotic release modulator itself has to be manufactured regularly because the osmotic release modulator itself releases the drug by a very sophisticated mechanism of action, otherwise it may cause a dose dumping phenomenon or irregularity due to breakage in vivo. It may also represent a phosphorous emission pattern. Therefore, the osmotic release control mechanism has a disadvantage in that the production process is complicated and expensive.

In addition, the osmotic release control mechanism is not efficient in terms of bioavailability of the active ingredient because the total amount of the drug contained in the formulation itself is not released and about 10% of the dose remains in the release mechanism and is not absorbed. none. In addition, the device has a lag time of about 2 hours for hydration and expression of osmotic pressure in vivo, and thus, the expression of the drug is delayed, which is not preferable in terms of drug efficacy. John S. Grundy and Robert T. Foster, The Nifedipine gastrointestinal therapeutics stem (GITS). Evaluation of pharmaceutical, pharmacokinetic and pharmacological properties. Pharnncoki net. 1966 Jan; 30 (1): 28-51].

Therefore, in order for the sustained-release preparations to meet the desired requirements, certain criteria must be met:

That is, firstly, the sustained-release preparations exhibit uniform and reproducible release over a long period of time, such as the zero-order release pattern, and the effect must be maintained continuously, and secondly, they must be easy to manufacture and economical.

Therefore, the present inventors have conducted various studies to find a new sustained release carrier for preparing a formulation that meets the purpose of such a sustained release formulation, and the side and monoglycerides, in particular oleic acid monoglyceride, are used as a hydrophilic component and a water-soluble medium. The present invention has been experimentally confirmed that it exhibits excellent physical sustaining effect by exhibiting gel physical properties indicating a zero order emission pattern upon contact with.

1 is a graph showing the drug dissolution test results of the sustained-release tablet prepared in Examples 1 to 4, the three-release tablet prepared in Comparative Example and the osmotic release modifier according to the present invention [-●-Example 1 Formulation, -○-Example 2 Formulation,-▲-Example 3 Formulation, -Δ- Example 4 Formulation,-■-Comparative Example Formulation,-□-Osmotic Release Regulator].

Accordingly, the present invention relates to a sustained release formulation formulated using monoglycerides as a sustained release carrier.

More specifically, the present invention relates to a sustained release formulation for oral administration containing (1) a pharmacologically active ingredient, (2) a monoglyceride as a sustained release carrier, (3) a hydrophilic ingredient, and (4) a pharmaceutical additive. It is about.

Hereinafter, each component of the sustained-release preparation of this invention is demonstrated concretely.

(1) Active Ingredient

In the sustained-release preparation of the present invention, any drug having a sustained release characteristic may be applied as the pharmacologically active ingredient. Particularly, from a pharmaceutical standpoint, a drug having a maximum maximum dosage of 200 mg or less is preferable. It is necessary to use an appropriate amount of sustained release carrier and other pharmaceutical additives in order to prepare a sustained release formulation, so if a single dose is formulated with too many drugs, the size of the actually produced product is too large to be unsuitable for oral administration. Because. Therefore, in order to obtain a dosage form suitable for oral administration, an active ingredient having a maximum maximum dosage of 200 mg or less is preferable. Possible drugs include antihypertensive agents and other cardiovascular agents, nonsteroidal anti-inflammatory drugs, asthma agents, sedatives, antibiotics, sedatives, expectorants, steroids, antihistamines and other drugs. In the preparations according to the present invention among these active ingredients, 1,4-dihi- dipypyridine and derivatives thereof having a maximum daily dose of 120 mg or less, particularly nifedipine, may be preferably used.

(2) sustained release carrier

Monoglycerides may be used as the sustained release carrier which is the most important component in the sustained release formulation of the present invention. Monoglycerides in the formulation of the present invention can be any of the monoglycerides that can be gel properties in contact with a hydrophilic component or a water-soluble medium, for example, glyceryl monooleate, glyceryl monostearate , Glyceryl monopalmitate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate and the like can be used. These monoglycerides may be used alone or in combination of two or more monoglycerides.

Monoglycerides which may be particularly preferably used in the sustained-release detergent of the present invention are glyceryl monooleate or a mixture of glyceryl monooleate and glyceryl monostearate.

(3) hydrophilic components

The third component of the sustained release formulation of the present invention includes a hydrophilic component, which is a component that assists the sustained release carrier in contact with a water-soluble medium in vivo to exhibit gel properties. In the present invention, as the hydrophilic component, one or two or more components selected from propylene glycol, glycerin, and polyethyleneglycol may be used. Among them, propylene glycol may be preferably used.

(4) pharmaceutical additives

Ingredients additionally added to the sustained release preparation of the present invention may include pharmaceutical additives that are acceptable for oral administration solid preparations, ie, neutral lime carriers, binders and lubricants.

Neutral dilution carriers that can be used in the sustained release formulations of the present invention can be used as a dilution carrier for the formulation of oral solid preparations, which are generally used in the pharmaceutical field. For example, lactose, dextrin, starch, microcrystalline cellulose calcium dihydrogen phosphate, calcium carbonate, sugars and silicon dioxide and the like can be used as the lime carrier.

Meanwhile, as the binder, any one of binders commonly used in the formulation of oral solid preparations may be used, for example, polyvinylpyrrolidone, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and the like. Can be.

Pharmaceutical additives that may be added also include glidants used for the purpose of increasing flowability. As the lubricant in the formulation of the present invention, any lubricant commonly used in the pharmaceutical field may be used, for example, zinc or magnesium salt of stearic acid.

Sustained release formulations of the present invention may also additionally be used as optional ingredients to further control the dissolution, as an optional release modulator that aids in the release of the active ingredient easily when the sustained release carrier is contacted with an aqueous medium. Examples of components that can be generally used for this purpose include, for example, hydrophilic polymers and surfactants, but hydroxypropylmethylcellulose may be preferably used.

In the sustained-release preparation according to the present invention, each component has a pharmacologically active ingredient, a sustained release carrier, a hydrophilic ingredient and a pharmaceutical additive in a ratio of 1: 0.05 to 10: 0.01 to 1: 0.5 to 50 by weight. And preferably in a ratio of 1: 0.1 to 5: 0.02 to 0.5: 1 to 20.

In addition, the compositions according to the invention illustrated in the following examples may also be mentioned as further preferred compositional examples.

Sustained release preparations according to the present invention having the composition as described above may be used in the form of solid dosage forms for oral administration, for example, tablets or the like, according to a conventional pharmaceutical preparation process. According to this method, for example, the pharmacologically active ingredient is uniformly mixed with a sustained release carrier, a hydrophilic ingredient and a diluent carrier, and any optional release controlling agent and a pharmaceutically acceptable conventional formulation aid, or is a sustained release carrier. It is pre-warmed and dissolved by adding a pharmacologically active ingredient to the mixture, followed by mixing homogeneously by adding a hydrophilic ingredient and a diluent carrier, and any optional release controlling agent and a pharmaceutically acceptable conventional formulation aid. A binder is added to the mixture to granulate, the resulting granules are dried and then dry mixed together with other ingredients such as lubricants and compressed into tablets. Alternatively, if the nature of the active ingredient is acceptable, all ingredients may be dry mixed to form a homogeneous mixture and then compressed to produce a tablet having the correct weight, thereby preparing a solid sustained release formulation for oral administration.

The sustained release preparation for oral administration according to the present invention containing the sustained release carrier described above exhibits a zero release pattern over 24 hours as described above, resulting in constant release and absorption in the digestive tract. Therefore, the effective blood concentration can be maintained in an equilibrium state to provide a daily disposable formulation as well as an advantage in that economic production can be performed due to the convenience of the process.

The present invention is explained in more detail by the following examples, but the present invention is not limited in any way by these examples.

Example 1

Ingredient Content [mg / tablet (total 240 mg)]

Nifedipine 30

Glyceryl Monooleate 20

Glyceryl Monostearate 5

Propylene Glycol 2.5

Calcium dihydrogen phosphate 157 .5

Hydroxypropylmethylcellulose 2208 11.5

Silicon Dioxide 7.5

Hydroxypropylcellulose-L 2

Zinc Stearate 4

Nifedipine, a pharmacologically active ingredient, is first warmed to dissolve and then mixed homogeneously with glyceryl monooleate as a sustained release carrier and glyceryl monostearate and propylene glycol as a hydrophilic component. It granulates, adding the excipient calcium dihydrogen phosphate, hydroxypropylmethylcellulose 2208, and the binder hydroxypropyl cellulose-L. After drying, the granules are pressed into tablets by adding the lubricants zinc stearate and silicon dioxide.

Example 2

Ingredient Content [mg / tablet (total 447 mg)]

Nifedipine 30

Glyceryl Monooleate 40

Propylene Glycol 2.5

Calcium dihydrogen phosphate 347 .5

Silicon Dioxide 15

Hydroxypropylcellulose-L 4

Zinc Stearate 8

Tablets were prepared according to the same method as in Example 1 using the above ingredients.

Example 3

Ingredient Content [mg / tablet (total 446 mg)]

Nifedipine 30

Glyceryl Monooleate 40

Propylene Glycol 5

Calcium Dihydrogen Phosphate 329

Hydroxypropylmethylcellulose 2 208 15

Silicon Dioxide 15

Hydroxypropylcellulose-L 4

Zinc Stearate 8

Tablets were prepared according to the same method as in Example 1 using the above ingredients.

Example 4

Ingredient Content [mg / tablet (total 447 mg)]

Nifedipine 30

Glyceryl Monooleate 40

Propylene Glycol 5

Calcium Dihydrogen Phosphate 295

Hydroxypropylmethylcellulose 2208 50

Silicon Dioxide 15

Hydroxypropylcellulose-L 4

Zinc Stearate 8

Tablets were prepared according to the same method as in Example 1 using the above ingredients.

Example 5

Ingredient Content [mg / tablet (total 300 mgg)]

Nifedipine 30

Glyceryl Monooleate 12.5

Glyceryl Monostearate 7.5

Propylene Glycol 2.5

Calcium Dihydrogen Phosphate 195

Hydroxypropylmethylcellulose 2208 10

Silicon Dioxide 15

Hydroxypropylcellulose-L 5

Microcrystalline Cellulose 27.5

Zinc Stearate 5

Tablets were prepared according to the same method as in Example 1 using the above ingredients.

Example 6

Ingredient Content [mg / tablet (450 mg total)]

Tipenadine 60

Pseudoephedrine 120

Glyceryl Monooleate 12.5

Glyceryl Monostearate 7.5

Propylene Glycol 2.5

Calcium Dihydrogen Phosphate 195

Hydroxypropylmethylcellulose 2208 10

Silicon dioxide 5

Hydroxypropylcellulose-L 5

Microcrystalline Cellulose 27.5

Zinc Stearate 5

Tablets were prepared according to the same method as in Example 1 using the above ingredients.

Comparative Example 1

Ingredient Content [mg / tablet (390.5 mg total)]

Nifedipine 30

Calcium Dihydrogen Phosphate 270

Hydroxypropylmethylcellulose 2208 60

Silicon Dioxide 15

Hydroxypropyl Cellulose-L 7.5

Zinc Stearate 8

Tablets were prepared according to the same method as in Example 1 using the above ingredients.

Experimental Example: Dissolution Test

Using the sustained-release tablets prepared in Examples 1 to 4 and Comparative Examples and commercially available osmotic release modifier Ada1at sustained-release tablet 30, the dissolution test was carried out according to the paddle method under the following conditions. The release pattern of nifedipine, the active ingredient from the formulation, was measured.

Dissolution test apparatus: Paddle method

Eluent: buffer (pH = 6.8) 10% + sodium lauryl sulfate 1.0%

Eluent Temperature: 37 ℃ ± 0.5 ℃

Elution amount: 900ml

Stirring Speed: 1OOrpm

Sampling time: every 2, 4, 6, 8, 10, 12, 24 hours, cnl and filtered with 0.45㎛ membrane filter to obtain a sample solution. After taking the eluate, add the same amount of fresh eluate.

Test conditions: All test procedures are performed with long wavelength light (λ420 nm).

Analysis method: Test according to the following liquid chromatography method.

Column: μ-Bondapak C ₁₈ (Waters)

Mobile phase: Acetonitrile: Water (60:40, v / v)

Flow rate: 1.5 ml / min

Detector: UV absorbance photometer (350 nm)

Injection amount: 20µl

Calculation of emissions: Calculation of cumulative emissions.

The measured results are shown in FIG. 1 attached. As can be seen from the results shown in FIG. 1, the sustained-release tablets of Examples 1 to 4 according to the present invention containing monoglycerides as sustained-release carriers are almost similar to osmotic release modifiers as comparative agents. The drug was continuously released while exhibiting a zero release pattern, but the sustained release tablet prepared in Comparative Example 1 without using a monoglyceride sustained release carrier did not exhibit a desired release pattern as a sustained release formulation.

As can be seen from the above test results, the sustained release preparation prepared using monoglycerides according to the present invention as a sustained release closure has both requirements required for the sustained release preparation, that is, (1) 0 It can exhibit uniform and sustained efficacy over a long period of time by showing tea extraction patterns, and (2) it is economically advantageous because it is manufactured by a simple method using monoglycerides which are inexpensive raw materials. Provides progress.

Claims (10)

Pharmacologically active ingredient, one or two or more hydrophilic ingredients selected from monoglyceride, propylene glycol, and glycethylene glycol as a sustained release carrier, and pharmaceutical additives based on the weight of 1: 0.05-10: 0.01-1: 0.5- Sustained release oral formulation containing 50 ratio. The sustained release oral preparation according to claim 1, wherein the pharmacologically active ingredient is nifedipine. The method of claim 1 wherein the sustained release carrier is in the group consisting of glyceryl monooleate, glyceryl monostearate, glyceryl monopalmitate, glyceryl monocaprylate, glyceryl monocaprate and glyceryl monolaurate Sustained release oral formulation, characterized in that one or two or more selected monoglycerides. The sustained-release preparation according to claim 3, wherein the sustained release carrier is glyceryl monooleate or a mixture of glyceryl monooleate and glyceryl monostearate. The sustained release oral preparation according to claim 1, wherein the hydrophilic component is propylene glycol. The preparation for sustained release oral administration according to claim 1, wherein the pharmaceutical additive is a diluent carrier, a binder, and a lubricant. The diluent carrier is selected from lactose, destrin, starch, microcrystalline cellulose, calcium dihydrogen phosphate, calcium carbonate, sugars and silicon dioxide, and the binder is polyvinyl pyrrolidone, gelatin, hydroxypropyl. Sustained release oral preparation, characterized in that selected from cellulose and hydroxypropylmethylcellulose, the lubricant is zinc stearate or magnesium stearate. The preparation for sustained release oral administration according to claim 1, further comprising a selective release modifier selected from water-soluble polymers and surfactants. The method of claim 1, wherein the sustained release oral dosage form is characterized in that the pharmacologically active ingredient, the sustained release carrier, the hydrophilic ingredient and the pharmaceutical additive are contained in a ratio of 1: 0.1-5: 0.02-0.5: 1-20 by weight. Preparations. The sustained release oral preparation of claim 1, formulated in the form of a tablet.