KR100601249B1 - Composition for producing controllable porous membrane of oral drug delivery system - Google Patents

Abstract

The present invention relates to a sustained release porous membrane-forming composition for oral drug delivery devices and oral sustained release drug delivery device prepared using the same, wherein the composition is a cellulose-based compound, polymethacrylate, semipermeable polyamide, semipermeable poly At least one film forming material selected from the group consisting of urethane and semipermeable sulfonated polystyrene.

As described above, the sustained release drug delivery device made of the sustained release porous membrane-forming composition of the present invention can control the release rate of the drug to efficiently and continuously release the drug in the gastrointestinal tract. In addition, depending on the thickness of the porous membrane, the composition of the membrane constituents, the amount of plasticizer, the amount of excipients, the release time of the drug can be controlled, and a small amount of the porous membrane is coated on existing tablets or granules to provide a basic sustained release formulation. It is easy to manufacture and reduce the cost of the product, and excellent membrane stability allows the manufacture of oral sustained release preparations that are not affected by long-term storage or temperature and humidity, and mass production is possible.

Porous, sustained release, drug delivery device

Description

Sustained release porous membrane-forming composition for oral drug delivery device {COMPOSITION FOR PRODUCING CONTROLLABLE POROUS MEMBRANE OF ORAL DRUG DELIVERY SYSTEM}

1 is a graph showing the drug dissolution trend with time of oral sustained release drug delivery device containing nifedipine, a poorly soluble drug prepared according to Examples 1 to 4 of the present invention.

Figure 2 is a graph showing the drug dissolution trend with time of the oral sustained release drug delivery device containing mesylic acid doxazosin which is a water-soluble drug prepared according to Examples 5 to 8 of the present invention.

Figure 3 is a graph showing the drug dissolution trend with time of oral sustained release drug delivery device containing nifedipine, a poorly soluble drug prepared according to Examples 9 to 12 of the present invention.

Figure 4 is a graph showing the drug dissolution trend with time of oral sustained release drug delivery device containing mesylic acid doxazosin which is a water-soluble drug prepared according to Examples 13 to 16 of the present invention.

Figure 5 is an electron scanning microscope photograph of the cross-section of the water-insoluble sustained-release membrane after all the drug release in the oral sustained-release drug delivery device of Example 1 of the present invention.

The present invention relates to a sustained release porous membrane-forming composition for an oral drug delivery device and an oral sustained release drug delivery device prepared using the same, and more particularly, for an oral drug delivery device that can control the release rate of a drug. A sustained release porous membrane forming composition and an oral sustained release drug delivery device prepared using the same.

[Prior art]

If the drug is absorbed too slowly and the drug's bioavailability is low or the drug is rapidly absorbed and lost out of the body too quickly, the rate of drug delivery should be controlled. To this end, a mechanical device or a pump using osmotic pressure, a device for controlling diffusion using a membrane, a device using a polymer material that is decomposed or decomposed in vivo, and various combinations thereof are used.

One type of coating pellet of indomethacin in a release-release indomethacin formulation in US Pat. No. 4,752,470 in a sustained release (controlled release) formulation, one of the osmotic pressure control systems that controls diffusion using an osmotic membrane. Sustained release formulations are described that include. This formulation adds a water-soluble polymer to the components of the water-insoluble membrane to inhibit drug release.

In addition, Korean Patent Laid-Open No. 2001-23358 discloses a method and apparatus for treating a mammalian organism for obtaining the desired physiological or pharmacological effects of local or systemic. The treatment device may comprise an internal core or reservoir containing an effective agent; A first coating layer permeable to passage of an effective agent; A second coating layer that is essentially impermeable to passage of the effective agent; And a third coating layer permeable to the passage of the effective drug. In other words, by controlling the release of the drug by alternating the layer that can pass through the effective drug and the layer that can not penetrate.

Korean Patent Laid-Open Publication No. 1997-32869 discloses a membrane-coated pellet containing diltiazem that can be taken once a day, and has a structure similar to that of a multilayer and a drug-containing film for controlling dissolution rate. The present invention relates to a pellet formulation having a composite multi-membrane structure in which a membrane membrane (similar matrix membrane) is combined and a method for producing the same.

The pellet formulation has a membrane layer consisting of a diltiazem containing layer on the core or granule alone and a mixture of water-soluble or water-insoluble polymers for elution control and a similar matrix membrane with a mixture between water-soluble or water-insoluble polymer and diltiazem. Is done. It is also characterized by the presence of 5-30% of the membrane. However, if the membrane is less than 5% of the drug sustained release drug delivery is impossible, if more than 30% there is a problem that the drug is not released.

Korean Patent Laid-Open Publication No. 2000-69800 describes a method for producing a porous matrix sustained release formulation by an emulsion method. That is, a method of preparing a porous matrix drug delivery agent is prepared by dissolving a polymer compound and a surfactant in an organic solvent, dispersing and stirring an aqueous solution containing a drug to prepare an emulsion, and then preparing it in a desired matrix form and immediately lyophilizing. By introducing a method for preparing a porous matrix as a method of drying at a room temperature for a certain time or using a lyophilizer, the method using an emulsion may have a problem of uniformity of the membrane and also a problem that the prepared polymer membrane is unstable or the size of pores increases. There is.

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems, and an object of the present invention is to provide an oral sustained release drug coating composition which can efficiently and continuously control drug release, and an oral sustained release drug delivery device manufactured using the same. .

In order to achieve the above object, the present invention provides an oral drug delivery device comprising at least one film forming material selected from the group consisting of cellulose-based compounds, polymethacrylate, semipermeable polyamide, semipermeable polyurethane and semipermeable sulfonated polystyrene To provide a sustained release porous membrane forming composition for.

The invention also relates to a core comprising a pharmacologically active ingredient; And a sustained release porous membrane comprising at least one film forming material selected from the group consisting of cellulose based compounds, polymethacrylates, semipermeable polyamides, semipermeable polyurethanes, and semipermeable sulfonated polystyrenes, wherein the film forming material comprises the core An oral sustained release drug delivery device is provided in an amount of 0.1 to 50 parts by weight based on 100 parts by weight.

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

The present invention relates to a sustained release porous membrane forming composition for use in forming a sustained release porous membrane in preparing an oral sustained release drug delivery device.

The sustained release porous film forming composition includes at least one film forming material selected from the group consisting of cellulose based compounds, polymethacrylates, semipermeable polyamides, semipermeable polyurethanes, and semipermeable sulfonated polystyrenes.

The cellulose-based compounds include unplasticized cellulose acetate, plasticized cellulose triacetate, triacetate cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethyl aminoacetate, cellulose acetate Group consisting of ethyl carbonate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose ether, cellulose acetate propionate, cellulose acetate octanate, cellulose acetate laurate, methyl cellulose and cellulose acetate with acetylated hydroxyethyl cellulose Can be selected from.

Polymethacrylate as the trade name Eudragit ^?? By Eudragit ^?? One selected from the group consisting of E, L, S, RL, RS, NE 30 D, FS, and FD may be used.

The acetate-based compound may be selected from the group consisting of aga acetate, amylose triacetate, beta glucan acetate, and triacetate of locust bean rubber.

Most preferably, the film forming material includes cellulose acetate and polymethylmethacrylate. At this time, the mixing ratio of the cellulose acetate and polymethyl methacrylate is preferably 2-3 to 1 to 1.5 weight ratio. Increasing the mixing ratio of cellulose acetate and polymethylmethacrylate delays the dissolution of the active ingredient, which is undesirable.

In addition, the sustained release porous film-forming composition of the present invention may further include a plasticizer and / or a disintegrant. The plasticizer may be selected from the group consisting of polyethylene glycol, glycerol, glycerol derivatives and fatty acid citrate derivatives.

The sustained release porous membrane-forming composition of the present invention preferably comprises the plasticizer in an amount of 1 to 40 parts by weight based on 100 parts by weight of the total composition.

In addition, the disintegrant may be selected from the group consisting of starch glycolide sodium, calcium-carboxymethyl cellulose and fatty acid glycol derivatives. The content of the disintegrant included in the composition for forming a sustained-release porous membrane of the present invention is suitably 0.1 to 0.5% by weight.

The sustained release porous film-forming composition of the present invention includes a solvent to perform a coating process. As such a solvent, one or more of ethanol, acetone, water, and the like may be mixed and used.

The process of coating the core containing the pharmacologically active ingredient with the sustained release porous membrane-forming composition having the above-described configuration may be carried out by any process of the general coating process. The drug delivery device produced is usually in the form of pellets and has a size on the order of 350-800 μm.

The oral sustained release drug delivery device prepared using the sustained release porous membrane forming composition of the present invention thus prepared includes a core comprising a pharmacologically active ingredient and a sustained release porous membrane formed of the composition. The core only needs to include the pharmacologically active ingredient, and does not necessarily have to be spherical, but may be in any phase, such as a granule phase or a tablet phase. The film forming material is preferably present in an amount of 0.1 to 50 parts by weight with respect to 100 parts by weight of the core, more preferably in an amount of 0.1 to 30 parts by weight, most preferably in an amount of 0.1 to 1 parts by weight. desirable. When the film forming material is less than 0.1 part by weight with respect to 100 parts by weight of the core, the film is not formed and there is a problem in that no film is formed, and when it exceeds 50 parts by weight, there is a problem that drug release does not occur.

The pharmacologically active ingredient may include a water soluble drug or a poorly water soluble drug. The poorly water-soluble drug means a drug having a solubility of 65% or less in an aqueous solution, and the water-soluble drug is a drug except for the poorly water-soluble drug, that is, a drug that is dissolved in an aqueous solution, and more specifically, a solubility of more than 65% in an aqueous solution. It means a drug having a. As the water-soluble drug having such physical properties, ionic drugs such as mesylic acid doxazosin, ambroxol hydrochloride, albuterol hydrochloride, deophylline, acetaminophen, and the like can be used. Fins, novastatin, prazosin, isradipine, metofurolol, oxybutylbutyl, dithiazem, analfree or verapamil can be used.

As described above, the oral sustained-release drug delivery device formed by coating with the sustained-release porous membrane-forming composition of the present invention can release not only water-soluble drugs but water-insoluble poorly-soluble drugs, and efficiently and continuously release the drugs in the gastrointestinal tract. can do. In addition to controlling the release time of the drug, mass production is possible. In addition, the drug is released into the gastrointestinal tract at a constant rate to sustain the pharmacological effect for a long time, and the release rate of the pharmaceutically active ingredient is controlled according to the type and amount of the substance that controls the thickness and the degree of porosity of the sustained-release porous membrane. Efficient control allows simple drug control compared to conventional oral sustained release drug delivery devices, and the process can be simplified.

The present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.

(Example 1: 1.02 parts by weight of sustained release porous membrane coating based on 100 parts by weight of drug core)

0.61 wt% cellulose acetate, 0.41 wt% Eudragit RL, 0.41 wt% polyethylene glycol, 0.41 wt% glycerol, 0.41 wt% hydroxypropylmethyl cellulose, 0.51 wt% water, 5.12 wt% ethanol, 51.2 wt% acetone, tree A sustained release porous membrane forming composition was prepared by mixing 0.06 wt% ethyl citrate and 0.2 wt% sodium starch glycolide.

A sustained-release drug delivery device was prepared by coating 40.66 wt% of the prepared pellet core containing the poorly soluble nifedipine as an effective drug using a fluidized bed coater.

(Example 2: 5 parts by weight of sustained release porous membrane coating based on 100 parts by weight of drug core)

3% by weight cellulose acetate, 2% by weight Eudragit RL, 0.4% by weight polyethylene glycol, 0.4% by weight glycerol, 0.4% by weight hydroxypropylmethyl cellulose, 0.51% by weight water, 4.1% by weight ethanol, 48.1% by weight acetone, tri A sustained release porous membrane-forming composition was prepared by mixing 0.09 wt% ethyl citrate and 0.2 wt% sodium starch glycolide.

The sustained release drug delivery device was prepared by coating 40.66% by weight of the prepared pellet core containing the poorly soluble nifedipine as an effective drug using a fluidized bed coater.

(Example 3: 10 parts by weight of sustained release porous membrane coating based on 100 parts by weight of drug core)

6% by weight cellulose acetate, 4% by weight Eudragit RL, 0.41% by weight polyethylene glycol, 0.4% by weight glycerol, 0.41% by weight hydroxypropylmethyl cellulose, 0.2% by weight water, 3.12% by weight ethanol, 45.2% by weight acetone, tri A sustained release porous membrane forming composition was prepared by mixing 0.06 wt% ethyl citrate and 0.2 wt% sodium starch glycolide.

40.66% by weight of the prepared pellet core containing the poorly soluble nifedipine as an effective drug was coated with a fluidized bed coater to prepare a sustained-release drug delivery device.

(Example 4: 0.5 parts by weight of sustained release porous membrane coating based on 100 parts by weight of drug core)

0.3% by weight of cellulose acetate, 0.2% by weight of Eudragit RL, 0.41% by weight of polyethylene glycol, 0.41% by weight of glycerol, 0.41% by weight of hydroxypropylmethyl cellulose, 0.51% by weight of water, 5.22% by weight of ethanol, 51.6% by weight of acetone, tri A sustained release porous membrane forming composition was prepared by mixing 0.06 wt% ethyl citrate and 0.2 wt% sodium starch glycolide.

40.66% by weight of the prepared pellet core containing the poorly soluble nifedipine as an effective drug was coated with a fluidized bed coater to prepare a sustained release drug delivery device.

(Example 5: 0.5 parts by weight of the sustained release porous membrane coating based on 100 parts by weight of the drug core)

0.3% by weight of cellulose acetate, 0.2% by weight of Eudragit RL, 0.41% by weight of polyethylene glycol, 0.41% by weight of glycerol, 0.41% by weight of hydroxypropylmethyl cellulose, 0.51% by weight of water, 5.22% by weight of ethanol, 51.6% by weight of acetone, tri A sustained release porous membrane-forming composition was prepared by mixing 0.06 wt% ethyl citrate and 0.2 wt% sodium starch glycolide.

40.66% by weight of the prepared pellet core containing the water-soluble mesylic acid doxazosin as an effective drug was coated using a fluidized bed coater to prepare a sustained release drug delivery device.

(Example 6: 1 part by weight of sustained release porous membrane coating based on 100 parts by weight of drug core)

A sustained release drug delivery device was prepared in the same manner as in Example 1, except that a preparation pellet containing water-soluble mesylic acid doxazosin was used as an effective drug.

(Example 7: 5 parts by weight of sustained release porous membrane coating based on 100 parts by weight of drug core)

A sustained release drug delivery device was prepared in the same manner as in Example 2, except that a preparation pellet containing water-soluble mesylic acid doxazosin was used as an effective drug.

Example 8: 10% Sustained Release Porous Membrane Coating on Drug Core

A sustained release drug delivery device was prepared in the same manner as in Example 3, except that a preparation pellet containing water-soluble mesylic acid doxazosin was used as an effective drug.

(Example 9)

The same procedure as in Example 4 was carried out except that a pen coater was used.

(Example 10)

The same procedure as in Example 1 was carried out except that a pen coater was used.

(Example 11)

The same procedure as in Example 2 was carried out except that a pen coater was used.

(Example 12)

The same procedure as in Example 3 was carried out except that a pen coater was used.

(Example 13)

The same procedure as in Example 5 was carried out except that a pen coater was used.

(Example 14)

The same procedure as in Example 6 was carried out except that a pen coater was used.

(Example 15)

The same procedure as in Example 7 was carried out except that a pen coater was used.

(Example 16)

The same procedure as in Example 8 was carried out except that a pen coater was used.

Experimental Example 1

In order to measure the elution amount of the sustained release drug delivery device prepared according to Examples 1 to 16, it was analyzed under the following analysis conditions using HPLC. The results are shown in FIGS. 1 to 4, respectively.

Mobile phase: water / methanol / methyl cyanide = 1/1/1 volume ratio

Column: ODS-C18, 250 × 4.6mm, 5㎛ Flow Rate: 1.0 ml / min

Flow rate: 1.0 mL / min

Detector: 235 nm

Elution condition: 1% -SDS (sodium lauryl sulfate) solution, 900mL

As shown in Figures 1 to 4, it can be seen that the drug release rate with time can be adjusted according to the content of the film forming material. That is, it can be seen that as the film forming material increases, the drug dissolution rate with time decreases to show a linear graph.

In addition, after the release experiment is completed, the photomicrograph of the granules of Example 1 is shown in FIG. 5. Looking at the photo shown in Figure 5, it can be seen that after the drug is released the surface is porous.

As described above, the sustained release drug delivery device made of the sustained release porous membrane-forming composition of the present invention can control the release rate of the drug to efficiently and continuously release the drug in the gastrointestinal tract. In addition, depending on the thickness of the porous membrane, the composition of the membrane constituents, the amount of plasticizer, the amount of excipients, the release time of the drug can be controlled, and a small amount of the porous membrane is coated on existing tablets or granules to provide a basic sustained release formulation. It is easy to manufacture and reduce the cost of the product, and excellent membrane stability allows the manufacture of oral sustained release preparations that are not affected by long-term storage or temperature and humidity, and mass production is possible.

Claims (18)

1 part by weight of at least one film forming material selected from the group consisting of cellulose based compounds and polymethacrylates; And It comprises 1.06 to 2.16 parts by weight of an additive consisting of a plasticizer and a disintegrant, The plasticizer is one or more selected from the group consisting of polyethylene glycol, glycerol, glycerol derivatives and fatty acid citrate derivatives, and the disintegrant is 1 selected from the group consisting of sodium starch glycolide, calcium-carboxymethylcellulose and fatty acid glycol derivatives. More than one species, Sustained release porous membrane-forming composition for oral drug delivery devices. The method of claim 1, wherein the cellulose-based compound is unplasticized cellulose acetate, plasticized cellulose triacetate, triacetate cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethyl Aminoacetate, cellulose acetate ethyl carbonate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose ether, cellulose acetate propionate, cellulose acetate octate, cellulose acetate laurate, methyl cellulose and acetylated hydroxyethyl cellulose A sustained release porous membrane-forming composition for oral drug delivery devices selected from the group consisting of cellulose acetate. The sustained release porous membrane forming composition of claim 1, wherein the film forming material comprises cellulose acetate and polymethylmethacrylate. The sustained-release porous membrane-forming composition for oral drug delivery devices according to claim 3, wherein the film forming material comprises cellulose acetate and polymethyl methacrylate in a ratio of 2 to 3: 1 to 1.5 by weight. delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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