KR101794242B1 - Sustained-release oral liquid formulations - Google Patents

Abstract

The present invention provides a sustained-release oral liquid preparation containing a drug and a carboxyl group-containing enteric polymer, wherein the carboxyl group-containing enteric polymer is dissolved in a medium, and a process for producing the same.
The present invention can provide an effective and economical sustained-release liquid preparation by a simple method of dissolving an enteric polymer in a medium of a conventional liquid preparation. The liquid formulation of the present invention is solidified in the stomach to enable the sustained release of the drug, thereby reducing the dose and the number of drug administration, as well as protecting the stomach acid-inactivated drug from stomach acid, The gastrointestinal tract can be protected from the induced drug. The longer the residence time in the gastrointestinal tract is, the more the absorption window is confined to the upper gastrointestinal tract and the small intestine, and the bioavailability of the drug increases.

Description

Sustained-release oral liquid formulations < RTI ID = 0.0 >

The present invention relates to a novel liquid preparation, and more particularly, to a pharmaceutical composition for sustained release of a pharmacologically active ingredient contained in a preparation when the composition is orally administered into the body and which is capable of exhibiting a remarkably long- ≪ / RTI >

Oral liquid preparations are preparations in which a pharmacologically active ingredient (hereinafter referred to as a drug) is dissolved or dispersed in a medium suitable for oral administration. The main formulations belonging to the oral liquid preparations include liquid preparations such as liquid preparations, elixir preparations, main preparations, syrup preparations, oriental preparations, liquid preparations including Rimona daje, and dispersing agents such as emulsions and suspensions.

Oral liquid preparations are formulations that are taken by patients who are hard to swallow drugs such as children and elderly people, and are advantageous in that they can be administered in an appropriate dosage depending on their weight in comparison with solid preparations such as tablets and capsules .

Oral liquid preparations do not require the drug to be released to the outside as the solid preparation is disintegrated, and the drug efficacy is generally fast since the drug can be absorbed directly at the application site. However, depending on the drug, there is a drug which needs to be lengthened in the action time. In such a case, it may not be appropriate to use an oral liquid preparation. Oral liquid preparations may not be appropriate because it is difficult to slow the administration as in the case of solid preparations, even when the number of administrations is reduced in order to simplify the administration. In addition, drugs that are inactivated in the stomach or that cause side effects to the stomach are difficult to formulate with oral liquid preparations, since the drug may be exposed to gastric juice or affect the gastric juice. In addition, the liquid agent has a very short residence time in the stomach compared to the solid agent, and it is inappropriate to formulate the drug with a greater bioavailability of the drug as the stomach and the residence time in the small intestine become longer.

As long as the effect of the drug can be sustained after administration into the body, the number of times the drug is administered can be increased and the compliance with the medication can be enhanced. According to the report by Cocburnet et al. In 1987, the adherence compliance of 3 times a day was only 38%, but as the number of times of administration twice a day, once a day decreased, the adherence compliance was 69%, 90% (Cockburnet. Med. J. Australia 147: 324-328 (1987)). Therefore, in order to increase the adherence of the oral liquid formulation to the medication, the sustained release of the liquid formulation is required.

Accordingly, a new formulation has been developed which overcomes the disadvantages of the aforementioned oral liquid preparations. U.S. Patent No. 4,876,094 discloses a liquid formulation in which a dual coated theophylline core consisting of a first coating comprising edible fat and a second coating comprising zein for the sustained release of the drug is suspended in an acidic liquid medium . The patent discloses that the drug-containing solid phase portion constituting the suspending agent is coated as a sustained-release excipient in order to release the drug, thereby enabling the sustained release of the drug while having a liquid phase.

U.S. Patent Publication No. 2008-0145419 discloses that sucrose acetate isobutyrate can be used as a material that enables controlled release of a drug in a liquid state. The sucrose acetate isobutyrate dissolves in water to form a low viscosity material suitable for oral administration, and upon oral administration, the water quickly escapes from the material and leaves a high viscosity liquid material, It can be released gradually.

U.S. Patent No. 4,988,679 discloses a composition comprising a triglyceride of an alkanoic acid of medium chain length or of a purified acetylated monoglyceride, a polyglyceryl ester of a high HLB, and a colloidal silicon dioxide, which is insolubilized by a pharmaceutically acceptable polyvalent cation ≪ / RTI > which is capable of releasing the drug for an extended period of time. When the acid is added in a similar manner to that in the stomach, the clear supernatant is removed to form a solidified product, and the drug is gradually released from the solidified product to obtain sustained release do.

As described above, liquid formulations having sustained-release properties while being liquid form preparations have been developed. However, due to their economical efficiency and low sustained-release effects, slow release formulations have not been widely commercialized. Therefore, there is a continuing need to develop a sustained release liquid formulation that can be easily manufactured while exhibiting better sustained release properties and is economical.

Therefore, the inventors of the present invention have made intensive studies to develop a formulation that can effectively exhibit sustained release while being a liquid preparation, and as a result, it has been found that when a carboxyl group-containing enteric polymer is dissolved in a medium of a conventional liquid preparation containing a solution and a dispersant, And the present invention has been completed.

It is therefore an object of the present invention to provide a sustained release liquid formulation which is a liquid formulation and which is capable of slowly releasing the drug.

Another object of the present invention is to provide a method for producing the sustained release liquid preparation.

In order to achieve the above object, in one aspect, the present invention provides a sustained-release oral liquid preparation comprising a drug and a carboxyl group-containing enteric polymer, wherein the carboxyl group-containing enteric polymer is dissolved in a medium.

According to another aspect of the present invention,

Dissolving a carboxylic acid-containing enteric polymer in an aqueous electrolyte solution of a pharmaceutically acceptable pH 6-9; And

And dissolving the drug in the enteric polymer solution. The present invention also provides a method for producing the sustained release liquid preparation.

Hereinafter, the present invention will be described in more detail.

The sustained release liquid preparation according to the present invention is characterized in that a carboxyl group-containing intolerable polymer is dissolved in a medium of a conventional liquid preparation such as a solution or a dispersant.

The carboxyl group-containing enteric polymer is generally soluble in an electrolyte aqueous solution of pH 6-9 and is insoluble and solidified in an acidic environment of pH 1-2 as in the stomach. The sustained release liquid preparation according to the present invention contains the carboxyl group-containing enteric polymer dissolved in the medium, and when the oral preparation is solidified under strongly acidic conditions in the stomach to form a solid cargo, the drug contained in the liquid preparation together with the solid cargo Thereby causing the drug in the liquid preparation to be released. That is, the liquid preparation according to the present invention is characterized in that the enteric polymer, which has conventionally been used in an enteric coating, is contained in the liquid preparation for the first time to enable the sustained release of the active ingredient of the liquid preparation.

After the liquid formulation according to the present invention is solidified in the stomach to form a solid cargo upon oral administration, the solid cargo may stay in the stomach and the drug may be slowly released into the gastric juice through release from the solid cargo. In addition, when the solid cargo reaches the small intestine through the duodenum over time, the surrounding environment becomes pH 6-7, and due to the characteristics of the enteric polymer, the solid cargo is dissolved and the drug can be released. Since the residence time in the gastrointestinal tract is long, it takes a considerably longer time to release the drug from the preparation and absorb it into the body than the conventional liquid preparation. In addition, when the liquid preparation of the present invention is solidified in the stomach, it may float on the stomach lumen in the gastrointestinal tract and may take a long time to stay in the stomach. By this effect, the release of the drug and absorption in the body can be done slowly.

Examples of the carboxyl group-containing enteric polymer include cellulose acetate phthalate (CAP), cellulose acetate trimellate (CAT), cellulose acetate phthalate (CAT), and cellulose acetate phthalate Cellulose acetate butyrate (CAB), carboxymethylethylcellulose (CMEC), shellac, polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) Acid copolymers (Eudragit), or combinations thereof.

In the liquid preparation according to the present invention, the carboxyl group-containing enteric polymer should be dissolved in the medium. In order to dissolve the carboxyl group-containing enteric polymer, the medium is an electrolyte aqueous solution having a pH of 6-9, Can be suitably varied. The electrolyte may be any electrolyte which is pharmaceutically acceptable and capable of dissolving the enteric polymer. Examples of the electrolyte include sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, sodium pyrophosphate, potassium pyrophosphate, Sodium carbonate, ammonium hydrogen carbonate, potassium phosphate, sodium acetate, or a combination thereof.

The liquid preparation of the present invention may further include other release modifiers in addition to the enteric polymer to further increase the sustained release of the preparation. The release modifying agent may be contained in the preparation of the present invention by dissolving in the medium together with the enteric polymer and may be contained in the preparation of the present invention, for example, cyclodextrin, casein, povidone, hydroxypropyl methylcellulose (HPMC), diethyl phthalate (DEP) (DMP), xylitol, inulin, amylose, chitosan, chondroitin sulfate, dextran, guar gum, pectin, and xylan.

The cyclodextrin may be cyclodextrin, beta, gamma, or a combination thereof. Cyclodextrin may play a role in inhibiting drug release due to cyclodextrin blocking the gap of the net structure formed by solidifying the preparation in the stomach. The dissolution rate of the drug can be lowered.

The casein is a milk protein which is solidified at around pH 4. When the preparation according to the present invention reaches the gastrointestinal tract when orally administered, it solidifies with the enteric polymer and can further promote the sustained release of the drug.

The above-mentioned diethyl phthalate (DEP) and dimethyl phthalate (DMP) correspond to a plasticizer of an enteric polymer, and as the amount of diethyl phthalate (DEP) and dimethyl phthalate (DMP) increases, drug elution is delayed.

The xylitol, inulin, amylose, chitosan, chondroitin sulfate, dextran, guar gum, pectin, xylan, etc. are macromolecular polysaccharides which form a conjugation with the drug to lower the drug elution can see.

The pharmacologically active substance may be any drug which is required to be a solution and to be sustained. When the active substance is water-soluble, it can be formulated as a solution. When the active substance is water-insoluble, it is preferably formulated as a dispersant such as an oil or a suspension. Since the preparation of the present invention can be solidified in the gastrointestinal tract when taken orally and can capture the drug, it can protect the gastrointestinal tract from drugs that are inactivated by gastric acid in gastrointestinal tract from gastric acid or from drugs that cause side effects in the stomach Can be performed. Therefore, a drug which has been inadequate to be conventionally used as a liquid preparation since it is a drug which is inactivated in the gastrointestinal tract or causes gastrointestinal side effects can be usefully formulated as a liquid preparation of the present invention. In addition, medicines that should be administered at too frequent intervals due to a low half-life in the body can be formulated as a liquid preparation while increasing the administration interval. In addition, since the drug of the present invention can be slowly released through the enteric polymer solidified in the gastrointestinal tract, the absorption window is present in the upper gastrointestinal tract or the small intestine, The formulation of the present invention may also be useful for enhancing the bioavailability of a drug in which absorption of the drug is increased as the residence time of the drug increases.

The present invention relates not only to the sustained release of drugs with very short half lives but also to the effects of the gastrointestinal drugs lactobacillus, omeprazole, propoxyphene, meperidine, methadone, pentazocine, dexamethasone, estrogen, aldosterone, progesterone, hydrocortisone And drugs that cause gastrointestinal side effects, and the like. The non-steroidal anti-inflammatory analgesic may be selected from the group consisting of non-steroidal anti-inflammatory analgesics (NSAIDs) such as aspirin, ibuprofen, naproxen and ketoprofen, and acetaminophen. In addition, the drugs whose absorption window is present in the stomach or duodenum or whose residence time in the stomach and small intestine is longer and the absorption of the drug is increased include acyclovir, bisphosphonate, captopril, furosemide, metformin, gabapentin, L-dopa, , Or cyprofloxacin, but the present invention is not limited thereto.

The liquid preparation according to the present invention may be a formulation of a solution or a dispersant, and examples of the solution include elixir, a main tablet, a syrup, an oriental, and Rimona daje. Examples of the dispersion include emulsions and suspensions , But is not limited thereto. Methods for the preparation of such various preparations are well known to those skilled in the art, and the preparations according to the present invention can be prepared by adding the enteric polymer or other release modifiers to the medium ≪ / RTI >

The amount of the enteric polymer contained in the liquid preparation of the present invention is not particularly limited as long as it is appropriate for oral administration, but it may preferably include 0.1-20% by weight of the enteric polymer, From 0.5 to 6% by weight of the polymer and an additional release modifier, and a preferred amount of the release modifier is from 0.1 to 30% by weight.

The sustained release liquid preparation according to the present invention

Dissolving a carboxylic acid-containing enteric polymer in an aqueous electrolyte solution of a pharmaceutically acceptable pH 6-9; And

And dissolving or dispersing the drug in the enteric polymer solution.

If the sustained-release liquid preparation further comprises a release modifier other than the enteric polymer, the step of dissolving the release modifier may further include dissolving the release modifier in the enteric polymer solution. Wherein the release modifying agent is selected from the group consisting of cyclodextrin, casein, povidone, hydroxypropyl methylcellulose (HPMC), diethyl phthalate (DEP), dimethyl phthalate (DMP), xylitol, inulin amylose, chitosan, chondroitin sulfate, dextran, guar gum, , Xylan, and combinations thereof.

In order to dissolve the enteric polymer, an appropriate electrolyte known to be used for dissolving the enteric polymer used may be added to water to adjust the pH to 6-9, and then the enteric polymer may be added and dissolved. The dissolution can be promoted by stirring. Preferably in a water bath at about 80-100 DEG C for 10 minutes to 1 hour. The drug can then be added to dissolve or disperse, and appropriate warming and stirring can be carried out. In addition, when a release modifier other than the enteric polymer is added, the release modifier may be added after the addition of the drug or before the addition of the drug. Even when an emission modifier is added, dissolution can be promoted by appropriate stirring and warming in accordance with the emission modifier used.

As described above, the present invention can provide an effective and economical sustained release liquid preparation by a simple method of dissolving an enteric polymer in a medium of a conventional liquid preparation. The liquid formulation of the present invention is solidified in the stomach to enable the sustained release of the drug, thereby reducing the dose and the number of drug administration, as well as protecting the stomach acid-inactivated drug from stomach acid, The gastrointestinal tract can be protected from the induced drug. The longer the residence time in the gastrointestinal tract is, the more the absorption window is confined to the upper gastrointestinal tract and the small intestine, and the bioavailability of the drug increases.

FIG. 1 is a graph showing the dissolution test of the acetaminophen solution prepared according to one embodiment of the present invention with different types of enteric polymer in a pH 1.2 solution according to the two-method paddle method to be.
FIG. 2 shows the dissolution test of the acetaminophen solution prepared according to one embodiment of the present invention in the pH 1.2 solution according to the two-method paddle method in the dissolution test method of the pharmacopoeia according to the present invention with or without addition of cyclodextrin Graph.
FIG. 3 is a graph showing the dissolution test of the acetaminophen solution prepared according to one embodiment of the present invention by varying the amount of cyclodextrin in the pH 1.2 solution according to the two-method paddle method to be.
Fig. 4 is a graph showing the dissolution profile of acetaminophen solution prepared according to one embodiment of the present invention, with or without addition of cyclodextrin, polyvinylpyrrolidone, and hydroxypropylmethylcellulose, Which is a graph showing the results of dissolution test in a pH of 1.2.
FIG. 5 shows the results of elution test of acetaminophen solution prepared according to one embodiment of the present invention in the amount of hydroxypropylmethylcellulose in pH 1.2 solution according to the two-method paddle method in the dissolution test method of the pharmacopoeia Fig.
FIG. 6 is a graph showing the dissolution test of the acetaminophen solution prepared according to one embodiment of the present invention by varying the amount of acetaminophen in the pH 1.2 solution according to the two-method paddle method to be.
FIG. 7 is a graph showing the dissolution test of L-set lysine and an asclover sustained release liquid prepared according to an embodiment of the present invention in a pH 1.2 solution according to the two-method paddle method in the dissolution test method of the pharmacopoeia.
FIG. 8 shows the result of dissolution test of the asclover sustained release liquid prepared according to one embodiment of the present invention in the order of addition of drug and cyclodextrin in pH 1.2 solution according to the two-method paddle method in the dissolution test method of the pharmacopoeia Fig.
FIG. 9 is a graph showing the results of dissolution test of the asclover sustained release liquid prepared according to one embodiment of the present invention in the pH 1.2 solution according to the two-method paddle method in the dissolution test method of the pharmacopoeia according to the present invention with or without addition of casein or inulin Fig.
FIG. 10 shows the dissolution test of the asclover sustained release liquid prepared according to one embodiment of the present invention in different compositions of casein, inulin, xylitol, and enteric polymer according to the two-method paddle method Fig.
FIG. 11 is a photograph of a lactic acid bacteria solution prepared according to an embodiment of the present invention, observed and photographed with an optical microscope after being subjected to different periods of time in which the solution was kept at a pH of 1.2.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these embodiments are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Example  One: Acetaminophen Sue castle Liquid  Manufacturing and testing (1)

(One) Sue castle Liquid  Produce

3% by weight of CAP (cellulose acetate phthalate), HPMCP (hydroxypropylmethylcellulose phthalate) or HPMCAS (hydroxypropylmethylcellulose acetate succinate) as an enteric polymer was added to 100 mL of an aqueous 0.1N NaHCO ₃ solution, And the mixture was stirred for about 30 minutes while heating in a water bath at 100 캜 to dissolve the enteric polymer.

4 g of acetaminophen was added to the insoluble polymer solution, followed by heating and stirring in a water bath for about 15 minutes to dissolve the solution, followed by cooling to complete the solution.

* (2) Leaching test method

The dissolution test was performed according to the second method paddle method in the Korean Pharmacopoeia (ninth revision) dissolution test method. 5 ml of the above-prepared liquid agent was precisely taken out and placed in a dosing cup, the rotation of paddles was stopped in the elution machine, and a chemical solution was added. The dissolution rate was calculated by measuring the concentration of acetaminophen released at 900 ml of Pharmacopoeia pH 1.2, the rotation speed of the paddle at 50 rpm, and the ultraviolet absorption spectrophotometer at 243 nm. The results are shown in Fig.

According to the results shown in Fig. 1, it was confirmed that the enteric polymer used for the preparation of the liquid preparation was released over 10-60 minutes from the first liquid corresponding to gastric juice. Therefore, it has been confirmed that the drug according to the present invention exhibits slow release of the drug in the gastrointestinal tract as compared with the simple liquid drug.

Example  2: Acetaminophen Sue castle Liquid  Manufacturing and testing (2)

(One) Sue castle Liquid  Produce

3% by weight of CAP or CMEC as an enteric polymer was added to 100 mL of an aqueous solution of 0.1 N NaHCO _{3, and the} mixture was stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

Optionally, 2 g of acetaminophen was added to the enteric polymer solution, and the mixture was heated and stirred in the water bath for about 15 minutes to dissolve. Then, 15 g of CD-S (a mixture of cyclodextrins?,?, And?) Was added thereto, and heating and stirring were carried out in the water bath for about 15 minutes to dissolve and cool to complete the solution.

(2) Elution test method

The dissolution rate was calculated by measuring the concentration of acetaminophen released by the same method as the dissolution test method in Example 1 above. The results are shown in Fig.

According to the results shown in Fig. 2, it was confirmed that the sustained release of the drug was further enhanced when the cyclodextrin was further added.

Example  3: Acetaminophen Sue castle Liquid  Manufacturing and testing (3)

(One) Sue castle Liquid  Produce

3% by weight of CAP, CMEC, HPMCP or HPMCAS as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

2 g of acetaminophen was added to the insoluble polymer solution, followed by heating and stirring in a water bath for about 15 minutes to dissolve. Then, 15 g or 20 g of CD-S (a mixture of cyclodextrins?,?, And?) Was added thereto, followed by warming and stirring in a water bath for about 15 minutes to dissolve and cool down to complete the solution.

(2) Elution test method

The dissolution rate was calculated by measuring the concentration of acetaminophen released by the same method as the dissolution test method in Example 1 above. The results are shown in Fig.

According to the results shown in Fig. 3, it was confirmed that when the amount of cyclodextrin was increased, the sustained release tended to increase.

Example  4: Acetaminophen Sue castle Liquid  Manufacturing and testing (4)

(One) Sue castle Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

2 g of acetaminophen was added to the insoluble polymer solution, followed by heating and stirring in a water bath for about 15 minutes to dissolve. Subsequently, 30 g or 35 g of CD-S (a mixture of cyclodextrins a, b, and y, target) was added or 3% by weight of kollidon SR (BASF) or 3% by weight of metolose 60sh (ShinEtsu) In the above water bath, warming and stirring were performed for about 15 minutes to dissolve and cooled to complete the solution.

(2) Elution test method

The dissolution rate was calculated by measuring the concentration of acetaminophen released by the same method as the dissolution test method in Example 1 above. The results are shown in Fig.

According to the results of FIG. 4, when the amount of cyclodextrin was increased, the sustained release tended to increase, and when povidone or HPMC was added, the sustained release was further enhanced.

Example  5: Acetaminophen Sue castle Liquid  Manufacturing and testing (5)

(One) Sue castle Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

2 g of acetaminophen was added to the enteric polymer solution, and the mixture was heated and stirred in the water bath for about 15 minutes to dissolve. Then, 20 g of CD-S (a mixture of cyclodextrins alpha, beta, and gamma, product of KK) was added, and 2 g, 1 g, 0.5 g, or 0.1 g of metolose 60sh (ShinEtsu) was added and then heated and stirred For about 15 minutes to dissolve and cool to complete the solution.

(2) Elution test method

The dissolution rate was calculated by measuring the concentration of acetaminophen released by the same method as the dissolution test method in Example 1 above. For the dissolution test, when the pellets were stopped by rotating the pellet and the pellets were slowly poured into the pellet, the surface area became solid like a wide surface strand and the pellet was solidified into a solid form at once. Due to these effects, accurate comparison of drug elution was difficult, but was applied in the same manner as possible. The results are shown in Fig.

5, the release rate of the drug was found to decrease as the amount of HPMC (metformose 60sh) increased.

Example  6: Acetaminophen Sue castle Liquid  Manufacturing and testing (6)

(One) Sue castle Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

1 g or 0.5 g of acetaminophen was added to the enteric polymer solution, and the mixture was heated and stirred in the water bath for about 15 minutes to dissolve. Then, 15 g of CD-S was added, followed by warming and stirring in the above water bath for about 15 minutes to dissolve, and the solution was cooled to complete the solution.

(2) Elution test method

The dissolution rate was calculated by measuring the concentration of acetaminophen released by the same method as the dissolution test method in Example 1 above. The results are shown in Fig.

According to the results shown in Fig. 6, it was confirmed that the dissolution profiles were similar, without being affected by the presence of acetaminophen. From these results, it is assumed that cyclodextrin does not encapsulate the drug, but the preparation of the present invention is caused to physically narrow the gap in the net structure formed upon solidification in gastric juice.

Example  7: Setridin  And Asclover Sue castle Liquid  Manufacturing and testing (1)

(One) Sue castle Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

To the enteric polymer solution, 500 mg of L-set lysine or acyclovir was added, and heating and stirring were carried out in the water bath for about 15 minutes to dissolve. Then, 15 g of CD-S was added, followed by warming and stirring in the above water bath for about 15 minutes to dissolve, and the solution was cooled to complete the solution.

(2) Elution test method

The dissolution rate was calculated in the same manner as in the dissolution test method in Example 1, except that the ultraviolet absorption spectrophotometer was measured under conditions of 231 nm for the settigin and 255 nm for the acyclovir. The results are shown in Fig.

According to the results shown in Fig. 7, both the sertraline and acyclovir solutions exhibited sustained release, while the asclover solutions showed higher sustained release.

Example  8: Asclover Sue castle Liquid  Manufacturing and testing (2)

* (1) The castle Manufacture of liquid agent

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

500 mg of acyclovir was added to the above-mentioned enteric polymer solution, followed by heating and stirring in a water bath for about 15 minutes to dissolve. Then, 15 g of CD-S was added, followed by warming and stirring in the above water bath for about 15 minutes to dissolve, and the solution was cooled to complete the solution. In addition, the addition of CD-S was preceded by the acyclover, and the same liquid preparation was prepared.

(2) Elution test method

The dissolution rate was calculated in the same manner as in the dissolution test method in Example 1 except that the condition of the ultraviolet absorptiometer was measured at 255 nm. The results are shown in Fig.

According to the results shown in Fig. 8, whether or not CD-S is added before the asclover has no significant influence on the sustained release of the liquid agent.

Example  9: Asclover Sue castle Liquid  Manufacturing and testing (3)

(One) Sue castle Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

500 mg of acyclovir was added to the above-mentioned enteric polymer solution, followed by heating and stirring in a water bath for about 15 minutes to dissolve. Subsequently, 15 g of CD-S was added, and 1, 2, 3 g of casein or 10 g of xylitol was added, followed by heating and stirring in a water bath for about 15 minutes to dissolve. Then, the solution was cooled to complete the liquid agent.

(2) Elution test method

The dissolution rate was calculated in the same manner as in the dissolution test method in Example 1 except that the condition of the ultraviolet absorptiometer was measured at 255 nm. The results are shown in Fig.

According to the results shown in Fig. 9, the addition of casein appears to increase the effect of sustained release compared to the case of no addition, and it was confirmed that the sustained release was further increased when xylitol was contained in a large amount.

Example  10: Asclover Sue castle Liquid  Manufacturing and testing (4)

(One) Sue castle Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

500 mg of acyclovir was added to the above-mentioned enteric polymer solution, followed by heating and stirring in a water bath for about 15 minutes to dissolve. Then, 15 g of CD-S was added, 3 g of casein and 5 g of xylitol; 2.5 g inulin; Or 3 g of casein and 2.5 g of inulin, followed by heating and stirring in the above water bath for about 15 minutes to dissolve. Then, the solution was cooled to complete the liquid agent.

Separately, 100 mL of 0.1 N NaHCO ₃ aqueous solution was prepared in the same manner using a total of 3 g of each of HPMCP, HPMCAS, CAP, CMEC and Eudragit L100 5.5 as an enteric polymer in total, acyclovir, 500 mg, CD-S 15 g and xylitol 10 g Respectively.

(2) Elution test method

The dissolution rate was calculated in the same manner as in the dissolution test method in Example 1 except that the condition of the ultraviolet absorptiometer was measured at 255 nm. The results are shown in Fig.

According to the results shown in FIG. 10, it was confirmed that the sustained release was properly controlled by the addition of casein, inulin, and xylitol, and it was found that the sustained release of the liquid can be controlled by changing the type of enteric polymer.

Example  11: Lactobacillus acidophilus  Lactobacillus Liquid  Manufacturing and Experiment

(1) lactic acid bacteria Liquid  Produce

3% by weight of CAP as an enteric polymer was added to 100 mL of an aqueous solution of 0.1N NaHCO _{3 and} stirred for about 30 minutes while heating in a water bath at 90 to 100 캜 to dissolve the enteric polymer.

After the enteric polymer solution was cooled, 1.7 g of Lactobacillus acidophilus lactic acid bacteria was added thereto, followed by stirring for 15 minutes to suspend, and 5 g of xylitol was added thereto, followed by stirring and cooling to prepare a liquid preparation.

(2) Acid resistance  Test Methods

10 ml of each of the lactic acid bacteria solution prepared in Example 11 was put into a pH 1.2 solution, and the solution was added to the solidified solution after 30, 60, 90 and 120 minutes, respectively. The residue was collected and dissolved in 0.1 N NaHCO ₃ aqueous solution, and then 0.1 N NaHCO ₃ was added thereto to make 100 ml. Each sample was observed under an optical microscope and photographed and shown in FIG. 11 (C: 30 minutes, D: 60 Min, E: 90 min, F: 120 min). For comparison, the specimen (A) after 120 minutes of dissolution of only lactobacillus acidophilus lactic acid bacteria in a pH 1.2 solution and the lactic acid bacteriostatic agent (B) prepared in Example 11 were also observed under an optical microscope, And is shown in Fig.

According to the results shown in Fig. 11, in the case of the photograph (A) corresponding to the simple liquid agent, live lactic acid bacteria were hardly observed, whereas in the acid resistance test of the lactic acid bacteria-containing liquid agent, It was confirmed that the lactic acid bacteria survived from pH 1.2 to 120 minutes.

AAP: acetaminophen
CD-S: Cyclodextrin

Claims (9)

Containing lactic acid bacteria and a carboxyl group-containing enteric polymer, wherein the carboxyl group-containing enteric polymer is dissolved in a medium. The method of claim 1, wherein the carboxyl group-containing enteric polymer is selected from the group consisting of cellulose acetate phthalate (CAP), cellulose acetate trimellate (CAT), cellulose acetate butyrate (CAB), carboxymethylethylcellulose (CMEC), shellac, polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylic acid copolymer (Eudragit), or a combination thereof. The formulation according to claim 1, wherein the medium is a pharmaceutically acceptable aqueous electrolyte solution of pH 6-9. The electrolyte according to claim 3, wherein the electrolyte is sodium bicarbonate, potassium bicarbonate, sodium hydroxide, sodium pyrophosphate, potassium pyrophosphate, sodium phosphate monobasic, ammonium bicarbonate, potassium phosphate, sodium acetate or a combination thereof The formulation. The method of claim 1, wherein the medium further comprises at least one compound selected from the group consisting of cyclodextrin, casein, povidone, hydroxypropyl methylcellulose (HPMC), diethyl phthalate (DEP), dimethyl phthalate (DMP), xylitol, inulin, amylose, chitosan, chondroitin sulfate, Wherein the release control agent selected from the group consisting of tran, guar gum, pectin, and xylan is further dissolved. 6. The preparation according to any one of claims 1 to 5, wherein the oral liquid preparation is an oral elixir, a main tablet, a syrup, an oriental, Rimonadense, an emulsion or a suspension. The preparation according to claim 5, wherein the enteric polymer is contained in an amount of 0.1 to 20% by weight and the release-controlling agent is contained in an amount of 0.1 to 30% by weight. Dissolving a carboxylic acid-containing enteric polymer in an aqueous electrolyte solution of a pharmaceutically acceptable pH 6-9; And
The method according to any one of claims 1 to 5, comprising the step of dissolving or dispersing the lactic acid bacteria in the enteric polymer solution. 9. The method according to claim 8, wherein the enteric polymer solution is mixed with cyclodextrin, casein, povidone, hydroxypropyl methylcellulose (HPMC), diethyl phthalate (DEP) Characterized in that it further comprises the step of dissolving a release modifier selected from the group consisting of dimethyl phthalate (DMP), xylitol, inulin, amylose, chitosan, chondroitin sulfate, dextran, guar gum, pectin and xylan.

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