KR100453288B1 - Squeeze-type osmotic drug delivery device for the controlled release of the drug - Google Patents

Abstract

The present invention relates to an osmotic drug delivery device of the squeeze type which continuously releases a drug by osmotic pressure, and more particularly, (a) a semipermeable sheath with a release port of at least one pharmacologically active ingredient, and (b) the semipermeable sheath. A squeeze-like osmotic composition, comprising: a squeeze expansion layer containing a swellable polymer and an osmotic agent and containing a disk with a gauze aperture; and (c) a pharmaceutical composition located within said semipermeable shell and containing a pharmacologically active ingredient. A drug delivery device comprising a squeeze-type controlled to continuously release the pharmacologically active component through the release port by sequentially expanding the disc by water introduced through the semipermeable envelope and the release port when the drug delivery device is exposed to an aqueous environment. A squeeze type osmotic drug delivery device.

The drug delivery formulation according to the present invention can release the pharmacologically active substance in a linear order, so that compared with the conventional drug delivery formulation, it is possible to obtain a late release force and a pulsed type of programmed release as well as capillary phenomenon. It facilitates the inflow of water into the device to increase the release and therapeutic effect of the drug during the entire drug release time is also economically and industrially useful.

Description

Squeeze-type osmotic drug delivery device for controlled release of the drug {SQUEEZE-TYPE OSMOTIC DRUG DELIVERY DEVICE FOR THE CONTROLLED RELEASE OF THE DRUG}

[Technical Field]

The present invention relates to a squeeze-type osmotic drug delivery device useful for medical and livestock industry, and more particularly, to a squeeze swelling layer and pharmaceutical composition comprising a swelling agent and an osmotic agent in a semipermeable envelope and sequentially expanding in an aqueous environment. A squeeze-type osmotic drug delivery device comprising a layer is provided.

[Prior art]

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

Osmotic pressure control system of drug release, when water in digestive tract penetrates the semi-permeable membrane and penetrates into the system, it is mixed with the osmotic material in the system to generate osmotic pressure. To release the formulation. The osmotic drug release device mainly maintains the therapeutic concentration of the drug in tissues or blood by adjusting the drug release and extending the drug release time to have a primary release rate, or a primary release rate when it is difficult to obtain the release rate. Aim to The advantage of an osmotic drug delivery system is that the drug is released at a constant rate regardless of the motility of the gastrointestinal tract and pH. In addition, since the drug reaches the gastrointestinal membrane in a solution state, it is easy to absorb, and there is an advantage in reducing gastrointestinal irritation and toxicity.

Conventionally known oral osmotic drug delivery systems (oral osmotic drug delivery system) are US Patent Nos. 3,845,770, 3,916,899, 4,111,202, 4,327,725, 4,612,008, 4,765,989, 4,783,337, 5,082,668, 5,830,501 and the like. Metotrolol, salbutamol, nifedipine, pseudoephedrine, verapamil, and theophylline are examples of products commercialized by the osmotic drug delivery system. There are many drugs under development. Adalat (trade name), a typical osmotic drug delivery agent, is a semi-permeable membrane coated on the outer wall of a tablet consisting of a drug, an osmotic salt and a hydrophilic polymer, and is applied to salts and hydrophilic polymers that induce osmotic pressure when contacted with an aqueous environment. Water is absorbed through the semipermeable membrane, and the osmotic pressure generated by the absorbed water causes the drug to be constantly released into the outlet.

Although conventional osmotic drug delivery systems have proven to be effective in many drug therapies, the rate of drug release of these devices tends to decrease over time, making it difficult to maintain a constant rate of late release and smooth drug delivery. It may not be possible, and the therapeutic effect of the drug is reduced before the desired treatment period is over. In addition, since the expression of the drug was delayed at the beginning of drug release and the amount of release was small, the drug could not be expected at the beginning of the administration. In addition, the osmotic drug release device itself must be produced constantly because the drug is released by a very sophisticated mechanism, otherwise it may show a dose dumping phenomenon or irregular release pattern due to damage in vivo.

U.S. Patent No. 5,780,057 discloses a drug delivery device comprising two or more cylindrical oral drug delivery devices containing a pharmaceutically active ingredient in one or more layers. Each layer is composed of compressed core and composed of polymer which shows expansion, gel, and erosion when it is in contact with aqueous environment.The rapid expansion of polymer in gastrointestinal tract increases the suspension time, and gelation and erosion It is a sustained release drug delivery device that delays or controls the release rate. However, the disadvantage of this device is that it is fast-acting and the effect of slowly releasing the drug for a long time is insufficient, and it is necessary to prepare each layer by several manufacturing processes to adjust the amount according to the release rate.

US Pat. No. 6,046,177 includes a layer containing a pharmacologically active ingredient and a layer for controlling drug release, and more particularly, a layer having a layer to help release the drug above and below the middle layer containing the pharmacologically active ingredient, respectively. Disclosed is an oral drug delivery device comprising a compression core consisting of three layers of a mold and an external semipermeable membrane. However, the device has a hassle to manufacture a drug layer divided into a rapid release layer and a sustained release layer, and must be prepared by separating the inner core and the drug layer surrounding it.

U.S. Patent Nos. 6,110,500 and 6,126,956 mix a water-soluble pharmacologically active ingredient, a water-soluble polymer carrier, and the like to penetrate the inside of a compressed manufactured core in a donut shape to form a cylindrical hole. A device coated with an inert shell is described. The device ensures constant release of water-soluble drugs through the cylindrical bore when the uncoated cylindrical bore is exposed to the aqueous environment. The device is effective for zero linear drug release, but has the problem that it can only be used in water-soluble drugs.

Therefore, the conventional osmotic drug delivery device is placed in an aqueous environment and at the same time the expansion layer is expanded to release the drug, so that the drug releases more than the required amount relatively early in the initial release and the amount of drug released in the late release to obtain a sustained zero order release rate That is, it is difficult to maintain a constant rate of drug release until drug release is complete, as well as to reduce the effect of drug initiation initially when drug expression is late, thus achieving a therapeutically effective concentration of drug. The disadvantage is that it is difficult.

Drug delivery formulations capable of releasing pharmacologically active ingredients in linear order, resulting in increased late drug release and programmed release of the pulse stream type, thus enhancing drug release and therapeutic effects during the full time of drug release. This is necessary.

In order to solve the problems of the prior art as described above, an object of the present invention is to provide an osmotic drug delivery device of the squeeze type with improved drug release properties.

It is another object of the present invention to provide an osmotic drug delivery device comprising a squeeze-expansion layer, a semipermeable shell and a pharmaceutical composition layer in which two or more disks having different degrees of expansion having the property of sequentially expanding over time are laminated. do.

Another object of the present invention is to provide an osmotic drug delivery device comprising a squeeze-expansion layer consisting of a squeeze-disc comprising a swelling agent or an osmotic agent in a gradual concentration gradient, a semipermeable shell and a pharmaceutical composition layer.

1 is a schematic cross-sectional view of an osmotic drug delivery device comprising a squeeze inflation layer consisting of a three-stage disc with different degrees of expansion and one outlet.

2 is a schematic diagram showing the drug release mechanism when an osmotic drug delivery device including a squeeze expansion layer consisting of a three-stage disc having different degrees of expansion and one discharge port is exposed to an aqueous environment.

Figure 3 is a schematic cross-sectional view showing a drug release mechanism and a cross-sectional view schematically showing an osmotic drug delivery device comprising a squeeze expansion layer consisting of a three-stage disc and two outlets.

Figure 4 shows an osmotic drug delivery device comprising a squeeze expansion layer consisting of a three-stage disk, Figure 4a is a device having one discharge port and the capillary induction component is included in the disk farthest from the discharge port, Figure 4b is a schematic cross-sectional view of a device having two discharge ports and the capillary inducing component is included in the central disk.

FIG. 5 is a cross-sectional view schematically showing an osmotic drug delivery device including a squeeze expansion layer including a disk containing a swellable polymer and an osmotic agent in a gradual concentration gradient to have a sequential degree of expansion, and two discharge ports; FIG. It is a schematic diagram showing.

Figure 6 is a graph showing the cumulative release of drug for 24 hours in the squeeze-type osmotic drug delivery device according to an example of the present invention.

* Symbol *

1, 31, 51: semipermeable outer layer

3, 33, 53: active ingredient outlet

15, 16, 17, 35, 36, 55: squeeze-disc

10, 30, 50: pharmaceutical composition layer

48: ingredient causing capillary phenomenon

In order to achieve the above object, the present invention

(a) a semipermeable sheath with a release port of the pharmacologically active ingredient, (b) a squeeze intumescent layer located within the semipermeable sheath and containing a swellable polymer and an osmotic agent, the disc having a central hole, and (c) the semipermeable sheath A squeeze-type osmotic drug delivery device comprising a pharmaceutical composition layer located within and containing a pharmacologically active ingredient,

When the drug delivery device is exposed to an aqueous environment, the squeeze-type osmoticity is controlled so that the disk is sequentially inflated by water introduced through the semipermeable outer shell so that the pharmacologically active ingredient is continuously released through the discharge port. A drug delivery device.

The invention (b) squeeze-type osmosis layer is squeeze-type osmotic, wherein the squeeze-inflated layer comprises two or more disks having different degrees of expansion stacked in order of magnitude of expansion so as to correspond to the outlets from the distal end of the pharmacologically active ingredient It relates to a sex drug delivery device.

The invention (b) the squeeze expansion layer comprises a disk containing the swellable polymer and the osmotic agent in a gradual concentration gradient so as to sequentially expand from the outlet of the pharmacologically active ingredient and corresponding to the outlet A squeeze-type osmotic drug delivery device.

The present invention relates to a squeeze-type osmotic drug delivery device (b) the disk of the squeeze expansion layer further comprises a capillary phenomenon causing component.

The present inventors have tried to develop a drug delivery device having the property of releasing the drug in stages at the same time as to improve the drug release properties, surprisingly the osmotic dilatation layer is expanded at the same time when exposed to the aqueous environment, the drug more than necessary in the initial release In order to overcome the problem of the release or the amount of release later than the required amount, it has been devised a squeeze expansion layer having the characteristic of expanding the osmotic expansion layer sequentially over time. In addition, the squeeze-disk layer having a squeeze-expansion layer of the capillary phenomenon is included in the squeeze-expansion layer so that the initial water inflow is increased in order to increase the initial release amount, the squeeze-disk layer with improved swelling rate of the swelling agent is sequentially given to the present invention. Was devised. The squeeze-disk layer has been completed in order to stack the two or more disks having a different degree of expansion, or to include a squeeze-disk containing a swelling agent or osmotic agent in the concentration gradient in order to sequentially give the expansion characteristics.

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

As used herein, the term "drug delivery device" means a dosage form that provides a means for delivering a pharmacologically active ingredient to a subject in need thereof.

As used herein, "pharmacologically active ingredient" means a compound, referred to as a drug and its equivalent, which includes any physiological or pharmacologically active ingredient that produces a local or systemic effect in an animal. The pharmaceutical composition layer including the active ingredient may include one or more active ingredients, and may be in the form of an uncharged molecule, a complex, or a pharmacologically acceptable salt thereof. It is also intended to include simple derivatives (eg, ethers, esters, amides, etc.) of the active ingredient, which can be readily hydrolyzed by the body's pH or enzymes and the like.

As used herein, the term "animal" refers to mammals, humans and primates (e.g., breeding animals such as sheep, goats, cattle, horses and pigs, or laboratory animals such as mice, rats and guinea pigs), fish, It is intended to include all birds, reptiles and the like.

As used herein, the term "squeeze dilatation layer" or "squeeze-disc" refers to the osmotic drug delivery device of the present invention when it is exposed to an aqueous environment, and subsequently expands to induce the pharmacologically active ingredient contained in the device to the outlet. Refers to an expanded layer or disc that performs a pushing function.

As used herein, the term "semi-permeable outer shell" or "semi-permeable membrane" does not pass through the solute inside the membrane, but refers to a membrane through which water or body fluids outside are passed.

As used herein, the term "causative component of capillary phenomenon" refers to a matrix-like, bundle-like, porous matrix in which the osmotic drug delivery device of the present invention rapidly enters water or body fluids when exposed to an aqueous environment. It refers to a high moisture absorption component of the hybrid series in which the polymer material or the inorganic material contained in the form, porous bundle or film, or porous film form is mixed.

The drug delivery device of the present invention comprises: (a) a semipermeable sheath having a pharmacologically active ingredient outlet, (b) a squeeze-disk having sequential expansion by water introduced into the semipermeable sheath in an aqueous environment, and (c) pharmacologically active It includes a pharmaceutical composition layer containing the component.

In one example of the invention, the drug delivery device may comprise one or more disks. For example, it can be two disks, three disks, five disks, seven disks or nine disks, or eleven disks, each having a different degree of expansion. It may preferably be a squeeze expansion layer comprising 2 to 5 discs. Squeeze expansion involving two to five disks is interrupted so that each time zone is based on a 24-hour period (e.g., for a three-layer disk, the lowest layer will work within the initial release time of 1-8 hours). The layer acts in the 8-16 hours and the top layer acts in the 16-24 hours) because it is easy to tailor the optimal conditions to obtain the optimal drug release pattern.

The squeeze-disk may be two or more having different degrees of expansion, and may also be a squeeze-disk including a swelling agent and an osmotic agent in a gradual concentration gradient to sequentially expand in an aqueous environment. Thus, from the opposite side of the outlet, the squeeze-disk can start swelling first and squeeze the pharmacologically active ingredient into the outlet while sequentially expanding. In a preferred embodiment of the present invention, the squeeze-disk having a high degree of expansion is laminated from the opposite side of the outlet when the drug outlet is in one direction, and the squeeze which is highly inflated from the center of the drug release device when the direction of the outlet is two. Disks can be stacked.

The movement of the squeeze-expansion layer constituting the drug delivery device according to the present invention is a pharmaceutical composition layer (A) inside the squeeze-disk layer (B, D, E) step by step as shown in Figures 2 and 3 , C) and squeezing the remaining squeeze-disk layer (B, D, E), the drug composition layer (A, C) outside has a characteristic principle. The stacking method of the squeeze-disk layer may be laminated by increasing the squeeze-disk layer as needed in the form of one, two, four, and five layers in addition to the three-layer lamination method. In addition, it is possible to initially include the "causing component of the capillary phenomenon" as a method for expanding the inflow of moisture into the device.

In addition to the laminating method of the squeeze-disk layer, in addition to the one or more laminating methods, the squeeze-disk layer is manufactured by stacking the squeeze-disk layer by layering in order of higher molecular weight, higher viscosity, or different concentrations of salts in progressive gradient form (E). The shortcomings of the law can also be solved.

One or more pharmacologically active ingredient release ports may be used, but more preferably, one or two opposite sides may be provided. The semipermeable shell has a discharge port through which the active ingredient is pumped, diffused, and moved. One or more drug release ports may be formed, preferably on either or both sides of the device. The semipermeable wall can be drilled mechanically or using a laser to form a passageway or passageways.

The thickness of the semipermeable skin of the present invention has a thickness in the range of 10 to 1,000 μm, and the content of the semipermeable skin component is about 1 to 50% by weight, preferably 2 to 30% by weight, based on the total weight of the drug delivery device. The range is not limited to the present invention, the thickness and content outside the above range can be adjusted according to the state of the formulation.

The size of the outlet will depend on the size of the core, the desired drug release profile and the number of outlets. In the case of one outlet, the size of the outlet can be, for example, in the range from 0.1 to about 2.0 mm in diameter, preferably from 0.3 to 0.7 mm in diameter. The diameter of the outlet may be less than or more than the diameter of the range depending on the state of the formulation. Drug release tools (3, 33, 53) of the squeeze-type sustained-release drug delivery system of the present invention is a needle needle having a diameter of 0.1 to 2.0 mm in the range of 0.5 to 2 mm, preferably 1 mm. The outlet can be made by drilling to depth. In addition, the shape of the discharge port is not limited to a circle can be triangular, square, oval or the like. The outlet is described in US Pat. No. 3,916,899, US Pat. No. 4,063,064, US Pat. No. 4,088,864, etc., in addition to US Pat. No. 3,845,770.

Preferred examples of the drug delivery device according to the present invention will be described in detail with reference to the structure of the osmotic drug delivery device of the present invention.

FIG. 1 shows (a) a semipermeable shell 1 having one discharge opening 3, (b) a disk having a high expansion from the far side from the discharge opening in the semipermeable shell is sequentially stacked, and in the semipermeable shell A cross sectional view of an osmotic drug delivery device comprising a squeeze expansion layer comprising three disks 15, 16, 17 with different degrees of expansion, and (c) a pharmaceutical composition layer 10. When the device is exposed to an aqueous environment, the disk is expanded by water introduced through the semipermeable shell and serves to control the ejection force of the pharmacologically active ingredient. , 16, 17) have different osmotic pressures and swelling degrees and act to push the drug composition layer towards the outlet as if squeezed. There is also an outlet 3 for smooth release of the pharmacologically active ingredient.

2 is a view illustrating a mechanism of releasing pharmacologically active ingredients when the osmotic drug delivery device shown in FIG. 1 is exposed to an aqueous environment. When the drug delivery device of FIG. 1 is in contact with the aqueous environment of the gastrointestinal tract, the osmotic inducer and excipient included in the discs 15, 16, and 17 and the semipermeable membrane 1 surrounding the outside of the formulation and the release port of the active drug ( 3) absorb moisture through the swelling agent in the pharmaceutical composition layer 10 and the disks (15, 16, 17) sequentially expand or gel to cause the release of the active drug. In particular, the squeeze expansion layer is expanded Swelling and squeezing the pharmaceutical composition layer 10 in the order of the size shown in FIG. 13 to slowly release the active ingredient out of the drug delivery device.

FIG. 3 shows (a) a semipermeable sheath 31 having two outlets 33, (b) a highly expandable disc being laminated in the semipermeable sheath sequentially from the center of the device, with different expansions in the semipermeable sheath. A squeeze expansion layer comprising three disks 35 and 36 having a degree; And (c) shows a cross-sectional view of the osmotic drug delivery device comprising a pharmaceutical composition layer (30). remind When the disks 35 and 36 are exposed to the aqueous environment, each of the disk layers 35 and 36 acts in sequence to squeeze and push the pharmaceutical composition layer 30 into the active drug through the bidirectional active drug outlet 33. To be released.

4a shows (a) a semipermeable shell 1 with one outlet 3; (b) a squeeze expansion layer comprising three disks (15, 16, 17) having different degrees of expansion in the semipermeable sheath sequentially stacked in the semipermeable sheath from the farthest from the outlet; Capillary action causing component 48 for enlarging the inflow of initial water; And (c) a cross-sectional view of the osmotic drug delivery device comprising the pharmaceutical composition layer 10. In the capillary phenomenon, the trigger component may be included in the lowermost portion of the squeeze-disc layer in the form of a film, a porous matrix, or a fiber bundle, or in the case of FIG. It may be contained in film form, porous matrix form or fiber bundles. When the device is exposed to an aqueous environment, the disk expands by water introduced through the semipermeable shell to control the release force of the pharmacologically active ingredient, thereby providing initial moisture through the component causing capillary action. The swelling ability is accelerated by expanding the inflow to the center of the device by taking the capillary-induced component, and it is in the shape of a donut with a hole in the center, and each layer 15, 16, and 17 is the active ingredient using different osmotic pressure and swelling ability. Squeeze and push to act. There is an outlet 3 for smooth release of the pharmacologically active ingredient. FIG. 4B shows the component 48 causing the capillary phenomenon incorporated into the squeeze-disk layer located centrally in the apparatus of FIG. 3.

5 shows (a) a semipermeable shell 51 having two outlets 53; (b) a squeeze-disk layer 55 laminated in the semipermeable shell and comprising an osmotic agent and an expanding agent in a gradual concentration gradient; And (c) an squeeze-type osmotic drug delivery device comprising a pharmaceutical composition layer 50. When the drug delivery device is in contact with the aqueous environment, the squeeze-disk layer 55 having a gradual concentration gradient gradually expands to squeeze and push out the pharmaceutical composition layer 50 while the active drug is released into the bidirectional discharge port 53. To be released.

The osmotic drug delivery device of the present invention is a semipermeable envelope in which the outlet of the pharmacologically active ingredient is formed, a squeeze expanded layer sequentially expanded by water introduced through the semipermeable envelope in an aqueous environment, and a pharmaceutical composition layer containing the pharmacologically active ingredient. It includes. Hereinafter, these components will be described in detail.

A. Squeeze Expansion Layer

The squeeze-disk layer of the squeeze-type osmotic drug delivery device according to the present invention contains a swelling agent and an osmotic agent, and is also a pharmacologically acceptable carrier, salt, binder, plasticizer, surfactant, capillary induction component. Components such as swelling aids, glidants, binders, dispersants, emulsifiers, wetting agents, dyes, and other excipients. The above components may be present as dispersions, particles, granules, or powders. Preferred squeeze expansion layers are solid disks in the form of donuts with a hole in the center.

The squeeze-disk layer 15, 16, 17, 35, 36, 55 may form a concentration gradient to have a gradual expansion or constitute a squeeze expansion layer with two or more disk layers having expansion to each other. Different degrees of expansion can be achieved by varying the type or concentration of the constituent material, for example, hydrophilic polymers with different degrees of water absorption, hydrogels or swelling substances, and salts with different concentrations. Even in the swellable polymer, different degrees of expansion can be obtained by varying the molecular weight or different viscosity. Due to the different swelling degree of each disk layer, it is to be different depending on the swelling degree according to the release time of the early, mid and late stage of the insect repellent. For example, in the case of discs with a gradual concentration gradient, the order of high molecular weight, the order of high viscosity, for example 100,000 g / mol for polyethylene oxide. (30-50 mPa s: 25 ° C.) to 8 million g / mol. (10,000-13,000 mPa s: 25 ° C.), 30,000 g / mol for polyvinyl alcohol. (4-7 mPa s: 25 ° C.) to 200,000 g / mol. (40-65 mPa s: 25 ° C.) may be used, or a squeeze-disk layer may be prepared by mixing in a gradual gradient form for each salt concentration difference. Specific numerical values and notations of these components are described in "Handbook of Pharmaceutical Excipients" Third edition: edited by Arthur H. Kibbe, in press APhA (American Pharmaceutical Association) and Pharmaceutical Press (2000).

The disk layers 15, 16, 17, 35, 36, 55 of the squeeze expansion layer are manufactured by standard compression-lamination manufacturing techniques. For example, a squeeze-disc layer is primarily a donut-shaped cylindrical mold with a hole in the center, whereby each layer is mixed with each component for performance, then the disk layers are sequentially stacked, or in a gradual concentration gradient. A mixed layer is prepared at 55 and then compressed into a solid layer.

Subsequently, the pharmaceutical composition layers 10, 30, and 50 are mixed with the components and drugs, and the squeeze-disc layers 15, 16, 17, 35, 36, and 55 formed in the cylinder-type mold are inserted. Next, the pharmaceutical composition layer is inserted into contact with the squeeze-disk layer and compressed to have a predetermined shape. The manufacturing method of the drug delivery device of the present invention is not limited to the above method for forming the formulation, and in addition to the above method, various methods such as conventional two-layer tablet compression techniques for the formulation may be appropriately selected and used. Can be.

The formulation of the basic squeeze-type sustained-release osmotic drug delivery formulation system was divided into a squeeze-disk layer (B, D, E) and a pharmaceutical composition layer (A, C) as shown in Table 1. Table 1 is illustrated by examples which do not limit the invention.

Ingredient Weight (wt% / tablet) Total weight (% by weight) Squeeze-Disk Layer Swelling agent (hydrophilic polymer) (a) Potassium chloride microcrystalline cellulose 26.3 weight% 13.2 weight% 10.5 weight% 50 wt% Pharmaceutical Composition Layer Pharmacologically active ingredient (nifedipine) hydrophilic polymer (b) potassium chloride microcrystalline cellulose 8.7% by weight 26.3% by weight 13.2% by weight 1.8% by weight 50 wt%

(a, b, c: hydrophilic polymers, hydrogels and swellable component materials include polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyacrylate, polymethacrylate , Gelatin, polyethylene oxide, polyvinyl pyrrolidone, etc.)

Ingredient Weight (wt% / tablet) Total weight (% by weight) Squeeze-Disk Layer (Two Steps) Swelling agent (hydrophilic polymer) (a) Potassium chloride microcrystalline cellulose 13.166.585.26 25 Swelling agent (hydrophilic polymer) (b) Potassium chloride microcrystalline cellulose 13.166.585.26 25 Pharmaceutical Composition Layer Pharmacologically active ingredient (nifedipine) hydrophilic polymer (c) potassium chloride microcrystalline cellulose 8.726.313.21.8 50

In addition to the above preferred component ratios, it is possible to adjust to other ratios according to the desired release form.

(1) swelling agent

As the swellable polymer, superabsorbent resins such as hydrophilic polymers or hydrogels and swellable materials may be used. In the present invention, the superabsorbent resin and the swellable component materials such as hydrophilic polymers or hydrogels which can be used in the drug delivery device for the controlled release of pharmacologically active ingredients are polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropylmethyl. At least one component selected from cellulose, hydroxypropyl cellulose, polyacrylate, polymethylacrylate, gelatin, carbohydrate, alginate, aluminum stearate gel, propylene glycol, glycerin and polyethylene glycols and polymer mixtures thereof Can be used.

Moreover, in order to achieve a desired degree of expansion using the molecular weight, the viscosity characteristic, etc. of each component, it can select suitably. Data such as molecular weight and viscosity are described in the following "Handbook of Pharmaceutical Excipients" Third edition: edited by Arthur H. KibbE, in press APhA (American Pharmaceutical Association) and Pharmaceutical Press (2000). For example, the swelling capacity of the swellable polymer is HPMC <polyvinylacetate <polyethylene oxide, and the swelling capacity of each swelling agent is also selected in the order of superior release ability at the same amount (e.g., molecular weight of polyethylene oxide). 100,000 <900,000 <800 million).

The content of the swellable polymer is not fixed, and the content can be adjusted according to the ability of each polymer. In one example of the present invention, the content of the swellable polymer included in the squeeze expansion layer may be used in the range of 1 to 80% by weight, preferably 1 to 50% by weight of the final weight of the pharmaceutical composition layer and the squeeze expansion layer.

(2) osmotic agents

In the present invention, the osmotic agent refers to a component that causes osmotic pressure, and any compound known to perform such a function to those skilled in the art may be used. Preferred osmotic agents include salts, sugars, urea or tartaric acid. For example, the osmotic salt includes sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium chloride or calcium bicarbonate, and as osmotic sugars, mannitol, glucose, lactose, sucrose and the like can be used. The components can also be used in combination in certain proportions by physical or chemical methods and are described in detail in US Pat. No. 4,968,507. The content of the preferred osmotic agent included in the squeeze expansion layer may be in the range of 1 to 50% by weight, preferably 5.0 to 30% by weight, based on the total weight of the pharmaceutical composition layer and the squeeze-disk layer.

(3) Capillary phenomenon causing component

When the osmotic drug delivery device of the present invention is exposed to an aqueous environment, water or bodily fluids are rapidly introduced into the device in the form of a matrix, a bundle, a porous matrix, a porous bundle or a film, or a porous film. There is a polymer-based material, or a hybrid-based fiber in which the inorganic material is mixed with the polymer material, for example, may be natural fiber or synthetic fiber, As a preferable example, cotton fibers, cellulose fibers, porous cotton fibers, porous cellulose fibers, synthetic fibers, synthetic fibers mixed with inorganic materials may be used. These forms may have the form of a general planar sheet, matrix, porous matrix, film, bundle, fibrous matrix, or twisted fiber bundle.

B. Pharmaceutical Composition Layer

(1) pharmacologically active ingredients

The pharmaceutical composition layer of the present invention may include only pharmacologically active ingredients or may further include various pharmacologically acceptable additives.

The pharmacologically active ingredient which can be delivered by the device of the present invention may include any active ingredient suitable for use as formulated in a sustained release formulation. In the present invention, the pharmaceutically active ingredient usually includes a local or systemic effect or other pharmacological or physiologically active ingredient causing such an effect in an animal. For example, pharmacologically active ingredients that can be used in the device of the present invention include antihypertensive and cardiovascular agents, antibiotics, sedatives, non-steroidal anti-inflammatory drugs, hyperlipidemia agents, expectorants, steroids, antihistamines, analgesics, antiarthritis agents, Antidepressants, antipyretics, immunosuppressants, proteins, peptides, anticancer agents, antitumor agents, neurostabilizers, hormones, sleeping pills, anesthetics, antidiabetics, antiparkinsonants, antimigraine, immunosuppressants and other drugs can be used, largely Is an unlimited inorganic or organic compound that acts on the peripheral nervous system, nervous system, cardiovascular system, blood circulation system, hormone system, immune system, reproductive system, digestive and secretory system, skeletal muscle, smooth muscle, adrenal and choline receptors, inhibitory histamine system, central nervous system Drugs and corresponding substances are included. The pharmacologically active ingredient may comprise a pharmaceutical composition, including a pharmaceutically acceptable carrier. Examples of pharmacologically active ingredients are described in Remington's Pharmaceutical Sciences, 16th, ED., 1980, Mack Publishing Co., Eaton, Pa. And The Pharmaceutical Basis of Therapeutics, goodman and Gilman, 6th ED., 1980, MacMillan Company, London and The Me are described in Index, 11th ED., 1989, Merck & Co, Rahway, N.J.

Derivatives such as esters, ethers, and amines of pharmacologically active ingredients may be used alone or in admixture with other compounds regardless of their degree of ionization and solubility. In addition, the pharmacologically active ingredient may be used when released from the device of the present invention, hydrolyzed by the body's pH or other metabolic processes, converted into its original form by an enzyme or converted into a biologically active form. The dissolved agent can be in various forms, such as a charged molecule, a charged molecule complex, or an ionic salt.

Suitable active ingredients for the preparations according to the present invention include nifedipine, a 1,4-dihydropyridine derivative useful as an antihypertensive agent and a cardiovascular agent, in consideration of the quantitative ratio of the sustained release carrier and other pharmaceutical additives. Likewise, an active ingredient with a maximum dose of 200 mg or less is suitable. By "therapeutically effective amount" in a pharmaceutical composition layer comprising a therapeutically effective amount of a pharmaceutically active ingredient is meant an amount of a pharmaceutically active ingredient that has been demonstrated to be sufficient to induce the desired effect of using the compound. The proportion of the active ingredient is determined by the desired time and aspect of the release and the pharmaceutical activity. The dosage may, for example, range from about 1 to 1,000 mg, and for example, in the case of nifedipine, a hypertension drug, the dosage may range from about 33 mg to 60 mg in sustained-release tablets.

(2) additive

Preferably, the pharmaceutical composition layer may include a swellable polymer and an osmotic agent. Swellable polymers and osmotic agents can be used for all used in the squeeze expansion layer. In addition, the content of the swellable polymer included in the pharmaceutical composition layer is 1 to 50% by weight, preferably 10 to 30% by weight, and the osmotic inducer is 1 to 50% by weight based on the total amount of the pharmaceutical composition layer and the squeeze expansion layer. Wt%, preferably 10-25 wt%. The microcrystalline cellulose serving as a binder used to facilitate moisture permeation or to provide a binding force to the swelling agent may be 0 to 5% by weight.

The pharmacologically active ingredient may be present in dispersions, particles, granules, or powders. In addition, the pharmaceutically active ingredient may further comprise a binder, dispersant, emulsifier or wetting agent, dyes, and the like. Other excipients such as lactose, magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol , Mannitol, polyethylene glycol, and other ingredients typically used as stabilizers or used in drug formulations.

In the present invention, excipients, such as pharmaceutical additives other than the above, that is, a binder (eg, microcrystalline cellulose, etc.), an expansion aid, a binder, a lubricant, and a surfactant may be used. Any component generally used in the pharmaceutical field may be used for the component used as an excipient. For example, microcrystalline cellulose, calcium carbonate, silicon dioxide, sorbitol, xylitol, sugars and starch can be used as diluents which are binders. Polyvinyl pyrrolidone, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium bicarbonate, agarose, polysaccharide gum such as carrageenan, gum arabic, xanthan gum and locust bean gum, etc. It can be used as, but not limited to.

Anionic, cationic and nonionic surfactants used in the present invention include sulfonic acid and sodium sulfate, sulfate amide, sulfate ether, sulfate esters, sulfonated ethers, alkylammonium salts, cetylpyridinium chloride, diethylmethyl cetyl ammonium chloride , Acylated polyamines, alkylated aryl polyether alcohols, polyethylene sorbitan esters, sorbitan monolaurate, fatty acid alcohol amines, campytol 888 ATO ™, and the like may be used, but is not limited thereto.

Those skilled in the art can achieve the desired effect by using excipients other than those disclosed above, and the extensive literature on suitable excipients provided in the art specifically refers to "Handbook of Pharmaceutical Excipients" Third edition: edited by Arthur H. Kibbe, in press American Pharmaceutical Association (APhA) and Pharmaceutical Press (2000).

C. Semipermeable Sheath

The semi-permeable membranes 12 and 35 surrounding the squeeze-disk layer and the pharmaceutical composition layer are pharmacologically acceptable and permeable to external gastrointestinal fluids, while essentially impermeable to drugs in the device, and can form thin films and pharmaceuticals. It is a substance that has no side effects on the active ingredient, animal body or host. In addition, the selective permeable membrane forming this wall may be insoluble and non-corrosive in the gastrointestinal tract or it may be biocorrosive after a predetermined period of bioerosion corresponding to the end of the active drug release period. In each case, it is permeable to gastrointestinal fluids rather than solutes, which are drugs in the device, and is suitable for the construction of osmotic powder devices.

Preferably, the semipermeable shell may include a semipermeable membrane forming component, a porosity controlling component, and other additives. For example, cellulose acetate of the semipermeable membrane forming material may use about 1 to 50% by weight, preferably about 2 to 10% by weight, more preferably 8 to 8% by weight of the total weight of the device. In addition, a porosity control component such as polyethylene glycol 200 may use about 0.5 to 5% by weight, preferably 1.5 to 3.0% by weight, and additives such as triacetin may be about 0.5 to 3.0% by weight, preferably 1.0 to 2.0. Weight percent can be used.

Such semipermeable membranes include, but are not limited to, semipermeable polymers such as cellulose-based compounds, semipermeable polyamides, semipermeable polyurethanes, and semipermeable sulfonated polystyrenes. Representative materials of the semipermeable sheath include commercially available unplasticized cellulose acetate, plasticized cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan 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, poly (vinyl Methyl) ether polymer, cellulose acetate octate, cellulose acetate laurate, methyl cellulose, locust congo Osmotic membranes prepared from one or more materials selected from the group consisting of triacetate, cellulose acetate with acetylated hydroxyethyl cellulose, hydroxylated ethylenevinylacetate, polymeric epoxides and mixtures thereof, alkylene oxide-alkyl Membranes known as osmotic and reverse osmosis membranes, such as glycidyl ether, polyurethane, polyglycolic acid and polycation-polyomion membranes known in the art. In general, useful membrane materials and device parameters are described, for example, in US Pat. Nos. 3,916,899 and 3,977,404.

Preferred semipermeable membrane materials include polyurethane, methyl cellulose, cellulose acetate, ethyl cellulose, and cellulose acetate butyrate. Most preferred is cellulose acetate. More preferably, a mixture of cellulose acetate, polyethylene glycol and triacetin can be used.

In addition, polyethylene glycol and triacetin may be used as components for controlling the porosity of the semipermeable membrane, but the present invention is not limited thereto. The additives used in the semipermeable envelope may generally use all additives added to the preparation of the semipermeable membrane. Consideration can be appropriately selected by those skilled in the art.

In one example of the present invention, the component of the semipermeable membrane solution contains, for example, 12.5 g of cellulose acetate, 3.75 g of polyethylene glycol, and 2.5 g of triacetin in 500 ml of acetone.

In the present invention, the application of the semipermeable membrane may be applied using a pan-coater to form a constant thickness of the air suspension in which the semipermeable membrane material and the solvent are compressed until a wall is formed on the outside, but is not limited thereto. In addition, as a method for applying a film, other film applying methods that can be used in the art, such as, for example, an immersion method, may be used.

Examples of suitable solvents used for forming the semipermeable membrane include inert inorganic and organic solvents. Such solvents are selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, aromatic solvents and mixtures thereof. Preferably, acetone, methanol, ethanol, methylenedichloride, ethanol, diacetone alcohol, isopropyl alcohol, chloroform, butyl alcohol, methyl acetate, ethyl acetate, n-hexane, n-heptane, ethylene glycol monoethyl acetate, ethyl ether And mixtures of acetone and water, acetone and ethyl alcohol, methylenedichloride and methanol, ethylene dichloride and methanol, such as benzene, toluene, carbon tetrachloride, methyl isobutyl ketone and the like, and an aqueous and non-aqueous mixture thereof. The solvent for forming the semipermeable membrane does not limit or limit the present invention.

All of the compositional ingredients that make up the sustained release osmotic drug delivery formulation system do not limit or limit the present invention.

The present invention preferably releases a water-soluble osmotic agent, a swellable excipient, and an excipient capable of controlling the release rate of the pharmacologically active ingredient, wherein 30% to 95% of the pharmacologically active ingredient is released within 24 to 30 hours at a predetermined time. A pharmaceutical composition having a coated semipermeable membrane is provided. The osmotic drug delivery device of the present invention, for example, releases about 2.0 (5 mg) to 40 wt% (200 mg) of nifedipine at an almost continuous rate of about 0.5 (0.2 mg) to 1.5 wt% (8.0 mg) per hour. A daily dosing regimen is provided wherein the total release of nifedipine per unit dose is about 5 to about 200 mg. In addition, nifedipine in the above range of 0.5 to 10.0% by weight of the total drug content is continuously released or programmed release tendency. Drug release characteristics of the drug delivery device according to the present invention are shown in FIGS. 6A and 6B.

Examples for osmotic drug delivery systems using the above components will be specified below. The following examples set forth below are merely illustrative of the present invention and are not limited to the protection scope of the present invention.

EXAMPLE

Example 1 Purification Comprising a Squeeze-Disk Layer Comprised of Three Speed Discs

In this embodiment, the osmotic drug delivery device of the squeeze type, consisting of three stages having different degrees of expansion, is manufactured as follows.

1-1: Preparation of Squeeze-Disk Layer

Osmotic tablet formulation was fixed to each tablet was squeeze-disk layer (B) and drug composition layer (A) 190 mg, 190 mg, respectively, the total amount was 380 mg (100% by weight). (15, 16, 17) components of each layer were mixed in a mortar with a component blending ratio for the preparation of the squeeze-disk layer as shown in Table 1 below.

Each compound powder was laminated in a disk-shaped mold of 8.18 mm in diameter in the order of the bottom, the middle and the top from the bottom, and compressed to 20 to 60 kgf / cm 2 using a compression molding machine. The content of each layer composition is shown in Table 3 below.

Swelling agent Potassium chloride Microcrystalline cellulose Sum Squeeze Layer lower Polyethylene oxide (Mw = 8 million g / mol) 8.77 4.39 3.50 16.66 stop Polyvinyl Alcohol (Mw = 30,000 g / mol) 8.77 4.39 3.50 16.66 Top Hydroxypropylmethylcellulose 606 8.77 4.39 3.50 16.66 Pharmaceutical Composition Layer Polyethylene oxide (Mw = 900,000 g / mol) 26.32 13.16 1.84 41.32 Sum 91.30

* Squeeze layer; Squeeze-Disk Layer

1-2: Preparation of the pharmaceutical composition layer

The pharmaceutical composition layer (A) was mixed with the components of the combination ratio shown in Table 3 and nifedipine 33 mg (8.7% by weight) in a mortar and pestle.

1-3: Tablet preparation comprising a pharmaceutical composition layer and a squeeze-disk layer

Insert the disk prepared in 1-1 in the stacking direction of a constant diameter 8.18 mm tablet in the stacking direction and add the compounding ingredient powder constituting the pharmaceutical composition layer, that is, the pharmaceutical composition layer is inserted into the disk layer The tablet form was once again pressurized with a compression molding machine of 20 to 60 kg _f / cm ² to have the final tablet form.

The tablets obtained above were coated with a semipermeable membrane. The composition for preparing the semipermeable membrane is 12.5 g each of 500 ml of acetone solvent such that the acetyl acetate content of cellulose acetate, polyethylene glycol 200, and triacetin is 62.5% by weight, 25.0%, and 12.5% by weight, respectively. / 5.0 g / 2.5 g was dissolved to prepare a coating solution. The prepared coating solution was evenly applied so that the weight of the semipermeable membrane per tablet was 40 mg. During the coating process the solvent was evaporated while heating to 35-45 ° C. After application, the tablets removed residual solvent under reduced pressure for 24 hours. The thickness of the semipermeable membrane had a distribution of 100 to 200 µm. The outlet was then drilled to a depth of 1 mm with a needle of 0.5 mm diameter in the center of the top of the tablet.

1-4: Drug Dissolution Experiment

Drug dissolution experiments were performed using a two-phase solution dissolution method. The eluate was poured into the elution tank for the eluent, 750 ml of tertiary distilled water and 250 ml of n-octanol to form a double solution layer of n - octanol and a water layer used to analyze nifedipine, a poorly soluble drug. The eluent temperature in the elution tank was adjusted to equilibrate (37 ± 0.5 ° C.). The tablet prepared in Example 1 was placed in the dissolution test basket and 1 ml of n-octanol in which nifedipine was dissolved at regular intervals (1, 4, 8, 12, 16, 20 and 24 hours). Collected and performed HPLC analysis. Other dissolution conditions were performed in accordance with the dissolution test method 2 (paddle method) of USP 23, and the two-phase solution dissolution method was prepared by Grundi, Andersson, Rogers and Foster, "Studies on dissolution testing of the nifedipine gastrointestinal therapeutic system. I. Description of a two-phase in vitro dissolution test, " J. Control. Rel. , 48 , 1-8 (1997). The amount of time release of nifedipine released from the tablet consisting of Example 1 is expressed as weight% (in 33 mg) below. In the following examples, the content indication is expressed in weight% unless otherwise specified.

Minutes 60 240 480 720 960 1440 Drug Release (%) 0.3-0.7 0.8-3.00 10.0-14.8 28.2-39.1 40.9-47.9 53.8-61.0

Example 2: Control of the Component Content Ratio of the Discs Constituting the Squeeze Expansion Layer

This is the case where the disk layer is manufactured by adjusting the compounding components constituting each layer 15, 16, 17 of the squeeze expansion layer based on the first embodiment. In the preparation of the squeeze expansion layer, the components of each layer (15, 16, 17), i.e., bottom: interruption: top, have a component ratio of 2: 1: 1, 1: 2: 1, 1: 1: 2 as follows. In each layer, the component ratios of the components were maintained in the same manner, while the content of each component was reduced or increased in the same proportion as a whole. The amount of hydrophilic polymer in each layer is from 8.77% to 6.58 to 13.16% by weight of Example 1, the amount of potassium chloride is from 2.39 to 10.0% by weight from 4.39% by weight of Example 1, the amount of microcrystalline cellulose is 3.50 of Example 1 The weight was adjusted to 0.92 to 9.21 wt%.

2-1, the components for the upper squeeze-disk layer 15 shown in Table 3 were mixed by adding polyethylene oxide (molecular weight 8 million g / mol.), Potassium chloride, and microcrystalline cellulose so that a total of 25.0% by weight. Next, the suspension 16 was mixed with polyvinyl alcohol (molecular weight 30,000 g / mol.), Potassium chloride, and microcrystalline cellulose so as to be 12.5% by weight in total. Finally, hydroxypropylmethylcellulose 606, potassium chloride, and microcrystalline cellulose were added and mixed at the top 17 so as to have a total of 12.5% by weight.

2-2 and the other one were 12.5% by weight of the one-stage squeeze-disk layer, 25.0% by weight of the two-stage squeeze-disk layer component, and 12.5% by weight of the three-stage squeeze-disk layer component.

2-3, the other was 12.5% by weight of the first stage squeeze-disc layer, 12.5% by weight of the two-stage squeeze-disc layer component, and 25.0% by weight of the three-stage squeeze-disc layer component.

The preparation method of the formulation used as a sustained release osmotic drug delivery system, the composition of a semipermeable membrane, and a drug dissolution test are the same as that of Example 1. The following is the time course of release of nifedipine in the device manufactured by the method of Example 2.

Minutes 60 180 300 480 960 1440 Drug Release (%) 2-1 0.3 1.5-2.6 14.2-19.5 35.6-41.8 44.0-50.2 56.6-67.5 2-2 0.1-0.2 0.9-1.6 7.7-9.4 25.5-26.8 35.5-38.3 45.6-60.1 2-3 0.2-0.5 3.5-4.1 10.7-13.4 28.6-29.5 42.5-44.5 61.2-62.0

Example 3 Preparation of Squeeze-Disk Layers with Different Osmotic Inducers

In each layer 14, 15, 16 of the squeeze-disk layer (B) based on Example 1, the hydrophilic polymer was polyethylene oxide (molecular weight 8 million g / mol.), Hydroxypropylmethylcellulose 606, polyvinyl pyrrolidone (Molecular weight: 360,000 g / mol.) And polyvinyl alcohol (molecular weight: 30,000 g / mol.) Were made constant with one kind of hydrophilic polymer, and layers (15, 16, 17) were formed according to the content of potassium chloride as an osmotic salt. . Preparation method of the osmotic drug delivery formulation, the composition of the semi-permeable membrane and the drug dissolution experiment was performed in the same manner as in Example 1.

Swelling agent Potassium chloride Microcrystalline cellulose Sum Squeeze Layer lower Polymer A " 8.77 6.32 1.58 16.67 stop 8.77 3.95 3.95 16.67 Top 8.77 1.58 6.32 16.67 Pharmaceutical Composition Layer Polyethylene oxide (Mw = 900,000 g / mol) 26.32 13.16 1.84 41.32 Sum 91.33

Example 3-1: Polymer A ^* in Table 6 is polyethylene oxide (molecular weight 8 million g / mol.)

Example 3-2: Polymer A ^* is hydroxypropylmethylcellulose in Table 6 606

Example 3-3: Polymer A ^* is polyvinyl alcohol (molecular weight 30,000 g / mol.) In Table 6.

Example 3-4: Polymer A ^* in Table 6 shows polyvinyl pyrrolidone (molecular weight 360,000 g / mol.)

Minutes 60 120 240 480 720 1440 Drug Release (%) 3-1 0.1-0.4 0.3-1.8 4.3-9.8 20.8-30.8 42.0-46.5 63.6-65.3 3-2 0 0 0 6.7-10.2 18.4-23.2 50.3-54.8 3-3 0.5-0.8 1.1-1.9 3.9-5.1 11.2-14.5 24.6-29.1 50.9-55.8 3-4 0 0 0 15.9-19.0 32.8-38.1 58.5-61.6

Example 4 Preparation of Squeeze-Disk Layers from Polymers Having Various Molecular Weights

Based on Example 1, each of the layers 15, 16, and 17 of the squeeze-disk layer (B) has one type of hydrophilic polymer, but each layer was configured by molecular weight. For example, polyethylene oxides having molecular weights of 8 million, 900,000, and 100,000 g / mol., Respectively, were laminated on each layer (15, 16, 17), or molecular weights of 360,000, 40,000, and 10,000 g, respectively. / mol. polyvinyl pyrrolidone was laminated to each layer (15, 16, 17).

The components of each squeeze-disk layer and the mixing ratio thereof are as shown in the following table. Was carried out.

Formulation according to molecular weight difference of polyethylene oxide, polyvinylpyrrolidone Squeeze Layer Swelling agent Potassium chloride Microcrystalline cellulose Sum lower Polymer A ^* 8.77 4.39 3.50 16.66 stop Polymer B ^* 8.77 4.39 3.50 16.66 Top Polymer C ^* 8.77 4.39 3.50 16.66 Pharmaceutical Composition Layer Polyethylene oxide (Mw = 900,000 g / mol) 26.32 13.16 1.84 41.32 91.30

(Polymer A ^* : 8 million g / mol polyethylene oxide (PEO) or 360,000 g / mol polyvinylpyrrolidone (PVP).

Polymer B ^* : Polyethylene oxide 900,000 g / mol. Or polyvinylpyrrolidone 40,000 g / mol.

Polymer C ^* : Polyethylene oxide 100,000 g / mol. Or polyvinylpyrrolidone 10,000 g / mol.)

Minutes 60 180 300 480 960 1440 Drug Release (%) 4-PVP 0 0 0 4.2-4.9 19.4-22.3 50.8-54.9 4-PEO 2.2-2.5 4.1-4.7 14.6-20.3 36.2-42.0 56.3-58.2 68.0-70.1

Example 5 Adjusting the Component Content Ratio of the Swelling Agent in Each Disk Layer

Each layer is based on a method in which a polyethylene oxide having a molecular weight of 8 million, 900,000, and 100,000 g / mol. Of Example 4 is laminated at a component ratio of 1: 1: 1 on each layer (15, 16, 17). The ratio of the components of the molecular weight was adjusted to 2: 1: 1 and 4: 1: 1, and the compositions are shown in Table 10 as Example 5-1 and Table 11 as Example 5-2, respectively.

Compounding components for each stage (15, 16, 17) of each squeeze-disk layer were mixed by adding polyethylene oxide, potassium chloride, and microcrystalline cellulose having a molecular weight of 8 million, 900,000, and 100,000 g / mol. The preparation method of the formulation used as a sustained-release osmotic drug delivery system, such as a pharmaceutical composition layer, is the same as that of Example 1.

When the content ratio of the swelling agent contained in each disk layer is 2: 1: 1 (unit: weight%) Squeeze Layer Swelling agent Potassium chloride Microcrystalline cellulose Sum lower Polyethylene oxide (Mw = 8 million g / mol.) 13.16 6.58 5.26 25.00 stop Polyethylene oxide (Mw = 900,000 g / mol.) 6.58 3.29 2.63 12.50 Top Polyethylene oxide (Mw = 100,000 g / mol.) 6.58 3.29 2.63 12.50

When the content ratio of the swelling agent contained in each disk layer is 4: 1: 1 (unit: weight%) Squeeze Layer Swelling agent Potassium chloride Microcrystalline cellulose Sum lower Polyethylene oxide (Mw = 8 million g / mol) 17.54 8.9 7.06 33.5 stop Polyethylene oxide (Mw = 900,000 g / mol.) 8.37 4.45 1.83 8.37 Top Polyethylene oxide (Mw = 100,000 g / mol.) 8.37 4.45 1.83 8.37

Minutes 60 240 480 960 1440 Drug Release (%) 5-1 3.2-4.7 10.8-15.3 35.4-39.0 59.1-66.1 75.8-85.3 5-2 2.3-4.0 9.7-10.0 38.9-40.1 58.6-60.1 70.2-73.1

Example 6 Polyethylene Oxide Molecular Weight Change of Pharmaceutical Composition Layer

In Example 4, a squeeze-disk layer (B) was obtained by stacking polyethylene oxides having a molecular weight of 8 million, 900,000, and 100,000 g / mol. At a component ratio of 1: 1: 1 on each end (15, 16, 17). ) And then using a polyethylene oxide having a molecular weight of 300,000 g / mol. In place of the polyethylene oxide having a molecular weight of 900,000 g / mol. Was prepared as in Example 1.

Minutes 60 240 480 960 1440 Drug Release (%) 0 7.1-7.7 24.5-28.9 39.6-45,8 66.8-72.2

Example 7 Changes in Composition of Semipermeable Sheath

The composition of the squeeze-disk layer and the pharmaceutical composition layer was prepared as in Example 6, and other conditions were the same as in Example 1. The semipermeable membrane component was controlled by changing the content of polyethylene glycol 200 forming the porosity of the semipermeable membrane, which is a component of the semipermeable membrane. Based on the composition of the semipermeable membrane of Example 1 to have a composition as shown in Table 6, it was dissolved in an acetone solvent to prepare a coating solution. In Example 1, the same procedure as in the preparation of the semipermeable membrane was carried out, but the weight of the semipermeable membrane and the diameter of the drug release port of each tablet were changed as follows. The prepared coating solution was applied so that the weight of the semipermeable membrane per tablet ranged from 40, 50, 60 and 70 mg, respectively, and the diameters of the drug release tool were 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm and 0.5 mm, respectively. It was drilled with a needle needle to have.

Outer layer composition (Unit: wt%) Cellulose acetate Polyethylene glycol Triacetin Semi-permeable weight Example 1 62.5 25.0 12.5 40 Example 7-1 62.5 25.0 12.5 50 Example 7-2 62.5 25.0 12.5 60 Example 7-3 62.5 25.0 12.5 70 Example 7-4 64.5 22.6 12.9 40 Example 7-5 66.7 20.0 13.3 40 Example 7-6 69.0 17.2 13.8 40 Example 7-7 71.4 14.3 14.3 40 Example 7-8 64.5 22.6 12.9 60 Example 7-9 66.7 20.0 13.3 60 Example 7-10 69.0 17.2 13.8 60 Example 7-11 71.4 14.3 14.3 60 Example 7-12 76.9 7.7 15.4 60

Example 8 Pharmaceutical Composition Layer Added Adjuvant

8-1: Add Citric Acid to the Pharmaceutical Composition Layer

8.68% by weight of citric acid was added to the pharmaceutical composition layer component of Example 6 to prepare a pharmaceutical composition layer.

8-2: Polyvinylpyrrolidone Added to the Pharmaceutical Composition Layer

8.68% by weight of polyvinylpyrrolidone was added to the pharmaceutical composition layer component of Example 6 to prepare a pharmaceutical composition layer.

8-3: Citric acid and polyvinylpyrrolidone added to the pharmaceutical composition layer

The same amount of citric acid and polyvinylidone were added to the pharmaceutical composition layer component of Example 6 at 8.68 wt%. Example 8 is a squeeze-disk layer of the same composition as Example 4, except that the composition of the drug composition layer and the outer skin layer.

The semipermeable membrane compositions having the components of Examples 7-4 and 7-6 were dissolved in acetone solvent to prepare a coating solution. The prepared coating solution was applied in such a way that the weight of the semipermeable membrane per tablet was in the range of 40 mg, respectively, and the method of preparing the formulation used as the osmotic drug delivery system except that the diameter of the drug release agent was 0.3 mm each. Same as

Pharmaceutical Composition Layer (Unit: wt%) Example 6 Example 8-1 Example 8-2 Example 8-3 Polyethylene oxide (Mw = 300,000 g / mol.) 26.32 17.64 17.64 8.96 Potassium chloride 13.16 13.16 13.16 13.16 Microcrystalline cellulose 1.84 1.84 1.84 1.84 Citric acid - 8.68 - 8.68 Polyvinylpyrrolidone - - 8.68 8.68

Minutes 60 240 480 720 960 1440 Drug Release (%) 8-1 (7-4) 1.6-2.4 4.4-8.4 15.7-28.5 38.0-48.4 55.8-60.4 61.3-64.7 8-2 (7-4) 2.4-3.0 6.5-14.3 28.0-34.2 45.9-52.1 55.7-62.7 66.2-69.0 8-1 (7-6) 0.6-0.7 6.9-7.4 17.3-23.3 32.5-41.6 48.3-57.1 64.8-69.4 8-2 (7-6) 0.5 1.6-3.4 11.5-16.1 27.3-29.2 42.9-43.5 61.1-62.0 8-3 (7-6) 0.8-0.9 5.8-6.4 10.4-18.6 23.7-35.2 38.1-53.5 55.0-69.8

Example 9 Squeeze-Disk Layer Including Two-Level Disks

Two layers of squeeze-disk layers having a molecular weight of 8,000,000 g / mol. The pharmaceutical composition layer used polyethylene oxide 300,000 g / mol as in Example 6, the components of the pharmaceutical composition layer and the manufacturing process of the tablet is the same as in Example 1. The composition of the semipermeable membrane was used in Example 1 and 7-5, 6, 7, and was used as a discharge oil tools 0.3, 0.4, 0.5 mm in diameter.

Two-stage squeeze-disk layer (unit: wt%) Squeeze Layer Swelling agent Potassium chloride Microcrystalline cellulose Sum lower Polyethylene oxide (Mw = 8 million g / mol) 13.16 6.58 5.26 25.0 Top Polyethylene oxide (Mw = 100,000 g / mol) 13.16 6.58 5.26 25.0 Pharmaceutical Composition Layer Polyethylene oxide (Mw = 300,000 g / mol) 26.32 13.16 1.84 41.3 Sum 91.3

Minutes 60 240 480 720 960 1440 Drug Release (%) 9-1 (Example 1) 0.3 mm 1.1-3.3 8.8-12.1 30.0-36.6 51.2-54.2 61.9-65.4 72.8-74.0 9-2 (7-5) 0.4 mm 1.0-1.7 5.4-12.2 22.0-29.9 36.6-47.4 52.2-60.8 69.0-73.5 9-3 (7-5) 0.5 mm 1.8-3.1 8.1-16.7 28.3-33.6 40.5-49.1 55.6-63.8 73.5-77.1 9-4 (7-6) 0.3 mm 0.2-0.5 1.3-2.8 13.4-16.2 29.2-33.0 46.1-52.3 61.0-65.1 9-5 (7-6) 0.4 mm 0.6-1.3 4.7-10.7 22.1-27.9 38.8-45.6 49.1-54.5 66.2-72.0 9-6 (7-7) 0.4 mm 0-0.3 5.8-6.9 14.2-21.1 30.7-39.4 48.7-54.4 65.7-69.5

Example 10: Sodium hydrogencarbonate added to the squeeze-disk layer

It has an osmotic drug delivery device comprising a squeeze-disk layer consisting of two layers as in Example 9, the pharmaceutical composition layer is the same as in Example 6, the semi-permeable membrane composition is Example 7-6, the drug discharge port was 0.3 mm . However, sodium bicarbonate was added to each of the two squeeze-disk layers in descending order from the bottom and had the following weight percentage (in weight of 380 mg except the membrane): 0.5%, 1.18%, and 1.84% by weight were added.

Minutes 60 240 480 720 1200 1440 Drug Release (%) 10-1 0 2.0-5.6 16.2-20.2 36.5-40.0 61.4-69.3 68.2-72.6 10-2 0 3.4-6.0 16.7-23.7 34.8-42.8 67.6-75.4 75.0-79.8 10-3 0 1.9-5.1 22.9-32.1 43.0-52.4 73.7-78.9 81.1-82.0

Example 11: Superporous Hydrogel Addition to Squeeze-Disk Layer

Instead of sodium hydrogen carbonate added to the squeeze-disk layer used in Example 10, superporous-hydrogel, Synthesis and characterization of superporous hydrogel composites in each of the two squeeze-disk layers: Journal of Controlled Release 65 (2000 ) 73-82.) Was carried out in the same manner as in Example 10, except that 0.26 wt%, 0.43 wt%, 0.79 wt%, 1.0 wt%, 1.58 wt% were added.

Minutes 60 240 480 720 1200 1440 Drug Release (%) 11-1 0.3-0.4 2.4-4.0 15.0-21.0 32.9-36.1 68.3-72.1 74.2-80.6 11-2 1.2-2.4 5.8-9.6 19.6-28.4 44.5-45.5 72.4-77.4 76.3-83.1 11-3 0.8-1.5 3.4-6.0 18.7-29.7 43.0-50.6 79.6-82.0 85.2-88.8

Example 12: Different polyethylene oxide molecular weight of the pharmaceutical composition layer

Squeeze-disk layer was prepared as in Example 9, the polyethylene oxide used in the pharmaceutical composition layer in Example 6 300,000 g / mol. Instead, one of 100,000 or 4 million g / mol. Of molecular weight was selected and used. Other components and ratios of the pharmaceutical composition layer are the same as in Example 6.

12-1: polyethylene oxide having a molecular weight of 100,000 g / mol. Of the pharmaceutical composition layer

The semipermeable membrane composition was set as Examples 7-5 and 7-6, the weight of the semipermeable membrane was 40 and 50 mg, and the drug release oil was 0.4 mm in diameter.

Minutes 60 240 480 720 960 1440 Drug Release (%) 12-1 (7-5) 50 mg 0.8-1.3 3.5-6.1 9.0-14.7 27.3-31.1 36.0-44.8 54.5-64.5 12-1 (7-6) 40 mg 0.8-1.7 3.2-6.4 10.2-13.6 20.3-27.7 31.7-37.5 44.6-49.8

12-2: polyethylene oxide having a molecular weight of 4 million g / mol. Of the pharmaceutical composition layer

The semipermeable membrane composition was set as Example 7-5 and 7-7, the weight of the semipermeable membrane was 40 and 50 mg, and the drug release oil was 0.4 and 0.5 mm in diameter.

Minutes 60 240 480 720 960 1440 Drug Release (%) 12-2 (7-5) -50 mg (0.4 mm) 0 1.3-2.1 13.9-16.1 28.0-30.2 41.4-45.4 54.5-59.7 12-2 (7-7) -40 mg (0.4 mm) 0 1.4-4.2 9.3-12.2 33.0-26.2 36.1-40.0 58.7-62.0 12-2 (7-7) -40 mg (0.5 mm) 0 1.7-5.5 11.3-15.6 29.1-35.1 39.6-47.1 60.0-64.6

Example 13: Adding locust bean gum to the top of the squeeze-disk layer

An osmotic drug delivery device was prepared in the same manner as in Example 9, except that 0.92 wt%, 1.97 wt%, and 2.1 wt% of locust bean gum as a binder was added only to the upper end of the squeeze-disk layer. . However, Examples 7-5 and 7-6 were used for the semipermeable membrane composition, and the weight of the semipermeable membrane was 40 and 50 mg, and the drug releasing agent was 0.4 mm.

Minutes 60 240 480 720 960 1440 Drug Release (%) 13-1 (7-5) 50 mg 0.2-1.3 5.5-7.3 17.9-20.5 33.8-40.6 51.3-60.9 75.1-78.7 13-2 (7-6) 40 mg 0.5-1.6 5.7-7.7 16.3-20.5 31.0-38.7 50.2-59.7 74.1-78.1

Example 14 Addition of Surfactant to Retard Release Rate in Pharmaceutical Composition Layer

To the constituents of the pharmaceutical composition layer of Example 9 was added 3.95% by weight of surfactant Camprytol 888 (compritol 888 ATO (trade name); Gattefosse (France)) having HLB 2 (Hydrophilic / Lipophilic Balance) A pharmaceutical composition layer was prepared in the same manner as in Example 9, except that the structure of the squeeze-disk layer was the same as in Example 9. However, the composition of the semipermeable membrane is Example 7-5, and 7-6, the weight of the semipermeable membrane was 40 and 50 mg, and the drug release oil was 0.4 mm.

Minutes 60 240 480 720 1200 1440 Drug Release (%) 14-1 (7-5) -50 mg 0.2-1.0 2.6-4.4 7.1-12.5 13.3-20.5 29.0-33.0 32.7-35.3 14-2 (7-6) -40 mg 0.4-1.3 3.0-4.8 9.6-15.4 16.6-24.6 30.2-37.8 33.7-40.1

Example 15: Polysaccharide addition to squeeze-disk layer

As in Example 9, the composition of the squeeze-disk layer and the pharmaceutical composition layer was configured. However, potassium chloride in the squeeze-disk layer was added by lactose and sucrose. The composition of the semipermeable membrane is the same as in Example 7-5, the weight of the semipermeable membrane is 40 mg, and the drug release milking tool is 0.4 mm.

Two-stage squeeze-disk layer containing polysaccharides (% by weight) Squeeze Layer Swelling agent Potassium chloride Microcrystalline cellulose Lactose Sucrose Sum lower Polyethylene oxide (Mw = 8 million g / mol) 13.95 - 2.63 4.21 4.21 25.0 Top Polyethylene oxide (Mw = 100,000 g / mol) 13.95 - 2.63 4.21 4.21 25.0 Pharmaceutical Composition Layer Polyethylene oxide (Mw = 300,000 g / mol) 26.32 13.16 1.84 - - 41.3 91.3

Minutes 60 240 480 720 1200 1440 Drug Release (%) 1.0-1.7 6.9-8.3 22.4-29.1 38.2-43.6 57.1-62.1 65.9-70.2

Example 16 Addition of Active Ingredient to Semipermeable Membrane Composition

The composition of the squeeze layer and the pharmaceutical composition layer was the same as in Example 15 except that 40 ml of distilled water, 20 ml of ethanol, 125 mg of potassium chloride, and 25 mg of nifedipine were added to the semipermeable membrane composition of Example 7-5. The composition content of the semipermeable membrane is as follows. As a solvent for preparing the semipermeable skin, 500 ml of acetone, 40 ml of distilled water, and 20 ml of ethanol were used.

Semipermeable Membrane Composition Polyethylene glycol Triacetin Cellulose acetate Potassium chloride Nifedipine Content (in 18.9 g) 19.84 weight% 13.23 weight% 66.14 wt% 0.66 wt% 0.13 wt%

Minutes 60 240 480 720 1200 1440 Drug Release (%) 1.4-2.0 12.1-17.4 29.2-35.1 45.5-49.6 61.8-65.4 70.1-73.5

Example 17 Addition of Ethanol to the Semipermeable Membrane Composition

100 ml of ethanol was added to 400 ml of acetone instead of 500 ml of acetone used as a solvent of the semipermeable membrane composition of Example 7-5. The conditions such as the other squeeze-disk layer and the pharmaceutical composition layer are the same as in Example 9.

Minutes 60 240 480 720 960 1440 Drug Release (%) 1.0-1.8 18.1-20.7 40.2-47.6 59.0-67.1 69.8-75.6 83.7-88.8

Example 18: Formulation with Two Outlets

A formulation used as a sustained release osmotic drug delivery system in the form of a squeeze-disk with bidirectional drug release (FIG. 3) was prepared as follows. Compounding ingredients were squeeze-disk layer (D) and drug composition layer (C) of 190 mg and 190 mg, respectively, and the total amount was fixed at 380 mg.

18-1: Preparation of Squeeze-Disk Layer and Pharmaceutical Composition Layer

In the preparation of the primary squeeze-disk layer (D), 8.77% by weight of polyethylene oxide (molecular weight 8 million g / mol.), Potassium chloride, so that the blending component for the suspension 35 of each squeeze-disk layer (D) is 16.66% by weight in total. 4.39% by weight and 3.50% by weight of microcrystalline cellulose were added and mixed. Next, 8.77% by weight of polyethylene oxide (molecular weight: 100,000 g / mol.), 4.39% by weight of potassium chloride, and 3.50% by weight of microcrystalline cellulose were added to the upper part 36 and the lower part 36 so that the total amount was 16.66% by weight. . The ingredients of each layer were mixed with a mortar and pestle. Each compound powder was laminated on a disk-shaped mold of diameter 8.18 mm in the layered order of (36-35-36) and compressed to 20 to 60 kgf / cm 2 using a compression molding machine.

Squeeze Layer Swelling agent Potassium chloride Microcrystalline cellulose Sum lower Polyethylene oxide (Mw = 100,000 g / mol) 8.77 4.39 3.50 16.66 stop Polyethylene oxide (Mw = 8 million g / mol) 8.77 4.39 3.50 16.66 Top Polyethylene oxide (Mw = 100,000 g / mol) 8.77 4.39 3.50 16.66 Pharmaceutical Composition Layer Polyethylene oxide (Mw = 300,000 g / mol) 26.32 13.16 1.84 41.32 91.30

18-2: Tablet manufacturing

The first prepared squeeze-disk layer (D) was inserted into the tablet mold of a constant diameter of 8.18 mm in the lamination direction, and the above-mentioned ingredient powders constituting the pharmaceutical composition layer (C) were added, that is, inside the disk layer. The overall tablet form was prepared by inserting a pharmaceutical composition layer and applying a pressure of 20-60 kg _f / cm ^{2 to} the compression molding machine once again to have the final tablet form (FIG. 3). The configuration of the semi-permeable membrane 31 is the same as in Example 7-5, and the weight of the semi-permeable membrane is 1 mm by the needle needle of 0.4 mm in diameter in the center of both sides of the upper and lower portions of the tablet. Perforated to a depth of

Minutes 60 240 480 720 960 1440 Drug Release (%) 0.5-1.4 2.4-6.75 16.0-25.4 38.1-41.1 52.8-56 81.1-84.0

Example 19 Addition of Capillary Induced Component to Squeeze-Disk Layer

19-1: Add capillarity-causing components to the bottom disc layer of a device with one outlet

The pharmaceutical composition layer and the squeeze-disk layer were prepared as in Example 9. However, in order to spread the initial water inflow into the squeeze-disk layer, 2.1 wt% of cellulose-based cotton fibers causing capillary action in a matrix form (as shown in FIG. 4A) (Example 19-1-A) ) Or 3.9 wt.% (Example 19-1-B) was added to the squeeze-disk layer. Preparation of other tablets is the same as in Example 1. The composition of the semipermeable membrane is the same as in Example 7-5, the weight of the semipermeable membrane is 40 mg, and the drug release oil tool is 0.4 mm.

Minutes 60 240 480 720 960 1440 Drug Release (%) 19-1-A 0.3-0.7 7-9.8 29.8-33.0 49.5-55.0 65.8-72.4 82.0-87.3 19-1-B 0.6-1.0 8.0-11.2 23.0-30.8 45.8-52.6 61.8-67.5 77.7-81.9

19-2: Addition of capillarity-causing components to the intermediate disk of a device with two outlets

The pharmaceutical composition layer and the squeeze-disk layer are the same as in Example 18. However, in order to diffuse the initial water inflow into the squeeze-disk layer, 2.1 wt% of cellulose-based cotton fibers causing capillary action in the middle portion of the squeeze-disc layer were added to the squeeze-disk layer. Preparation of other tablets is the same as in Example 18. The composition of the semipermeable membrane is the same as in Example 7-5, the weight of the semipermeable membrane is 40 mg, and the drug release oil tool is 0.4 mm.

Minutes 60 240 480 720 960 1440 Drug Release (%) 19-2 1.2-1.5 8.5-10.0 27.1-31.3 46.2-50.9 62.8-66.9 78.8-85.1

Example 20

In preparing the formulation having the bidirectional ejection opening of Example 18, except that the configuration of the three-stage squeeze-disk layer of Example 19, it was produced in 5, 7 layer type, etc., the manufacturing process of each squeeze-disk layer is 18 and the amount of each component (by molecular weight of hydrophilic polymer, by content of superporous hydrogel, by osmotic salt concentration, by binder and surfactant) The layers were constructed (ie, formed in the form of progressive gradient (E)). The manufacturing process and semipermeable membrane formation and formation of the ejection opening for the tablet including the following pharmaceutical composition layer configuration are the same as in Example 18. A drug delivery device including a five-speed disc was referred to as Example 20-1, and a drug delivery device including a seven-speed disc was referred to as Example 20-2.

Minutes 60 240 480 720 960 1220 1440 Drug Release (%) 20-1 0.3-0.5 6.8-13.2 18.5-29.3 27.6-32.8 37.6-50.1 74.3-82.6 20-2 1.2-3.6 4.3-15.1 12.7-19.4 30.6-35.6 35.8-43.7 53.0-57.1 63.7-75.8

The above embodiments do not limit the invention. It is apparent to those skilled in the art that the above preferred embodiments can be used to improve more effective performance.

Comparative Example 1

Drug release experiments were carried out in the method of Example 1 with Adelat Oros Tablet 30 from Bayer, containing 33 mg of nifedifen. The graph which shows the cumulative amount of drug release obtained with time is shown in FIG. According to FIG. 6, in Examples according to the present invention, it is possible to confirm the synergistic effect of early or late release and the stepwise release effect not observed in Comparative Example 1, which exhibits a zero order emission pattern similar to that of the tablet of Comparative Example 1. there was.

Minutes 60 240 480 720 960 1440 Drug Release (%) 0 4.8-7.6 18.5-21.3 32.7-37.1 44.4-51.2 64.9-73.1

In view of the above examples and effects, the present invention provides a squeeze-type sustained release drug delivery system that provides greater release force than the osmotic tack (Comparative Example 1) presented to date, thereby improving the effect of early and late drug release. In addition, it provides a pulsed release and sustained release force due to the stepped osmotic pressure of the squeeze-disc layer and can be phased out (Fig. 6b) to program the release conditions of the drug according to the characteristics of the drug. Therefore, it is possible to increase the efficacy of the drug to provide progress in the art.

The present invention provides a novel squeeze-type osmotic drug delivery device that continuously releases the drug, so that the pharmaceutically active substance can be a zero order linear release, and has an increase in late release power compared to conventional drug delivery formulations. In addition to obtaining pulsed-type programmed release, capillary action facilitates the inflow of water into the device, improving initial drug release, and confirming the release of the drug and the increase in therapeutic effect over the entire period of time. It can be economically and industrially useful.

Claims (23)

(a) a semipermeable sheath with at least one pharmacologically active ingredient release port, (b) a squeeze expansion layer in the semipermeable sheath comprising a swellable polymer and an osmotic agent and containing a disk with a central hole, and (c) A squeeze-type osmotic drug delivery device comprising a pharmaceutical composition located in the semipermeable envelope and containing a pharmacologically active ingredient, When the drug delivery device is exposed to an aqueous environment, the squeeze type of the squeeze type is controlled so that the disk is sequentially expanded by the water introduced through the semipermeable shell and the discharge port so that the pharmacologically active ingredient is continuously released through the discharge port. Osmotic drug delivery device. The squeeze of claim 1, wherein (b) the squeeze expansion layer comprises two or more disks having different degrees of expansion, stacked in order of magnitude of expansion so as to correspond to the openings from the distal opening of the pharmacologically active ingredient. -Type osmotic drug delivery device. 3. The disk of claim 2, wherein the semipermeable shell has two outlets located on opposite sides, and the squeeze expansion layer has two or more disks having different degrees of expansion stacked in order of magnitude from the center of the drug delivery device to correspond to the outlets. That comprises, squeeze-type osmotic drug delivery device. The squeeze expansion layer according to claim 1, wherein the (b) squeeze expansion layer contains a swellable polymer and an osmotic agent in a gradual concentration gradient so as to sequentially expand from the outlet of the pharmacologically active ingredient and includes a disk positioned to correspond to the outlet. Squeeze-type osmotic drug delivery device. The squeeze-type osmotic drug delivery device according to claim 1, wherein the drug delivery device is in the form of a tablet or pellet. The squeeze-type osmotic drug delivery device according to claim 1, wherein the semipermeable shell has a thickness of 10 to 1,000 m. The squeeze-type osmotic drug delivery device according to claim 1, wherein the active ingredient outlet has a diameter of 0.1 to 2.0 mm. The squeeze-type osmotic drug delivery device according to claim 1, wherein the semipermeable sheath comprises at least one semipermeable polymer selected from the group consisting of cellulose based compounds, semipermeable polyamides, semipermeable polyurethanes and semipermeable sulfonated polystyrenes. . 9. A squeeze-type osmotic drug delivery device according to claim 8, wherein said semipermeable sheath consists of one or more selected from the group consisting of polyurethane, methyl cellulose, cellulose acetate, ethyl cellulose, and cellulose acetate butyrate. 9. A squeeze-type osmotic drug delivery device according to claim 8, wherein said semipermeable sheath is a mixture of cellulose acetate, polyethylene glycol, and triacetin. The squeeze-type osmotic drug delivery device according to claim 1, wherein the content of the semipermeable shell is 1 to 50% by weight based on the total weight of the drug delivery device. The squeeze-type osmotic drug delivery device according to claim 1, wherein the disk of the (b) squeeze expansion layer further comprises a capillary inducing component. 13. The squeeze-type according to claim 12, wherein the inducing component of the capillary phenomenon is selected from the group consisting of cotton fibers, cellulose fibers, porous cotton fibers, porous cellulose fibers, synthetic fibers mixed with synthetic fibers and inorganic materials. Osmotic drug delivery device. The squeeze-type osmotic drug delivery device according to claim 1, wherein the pharmaceutical composition further comprises a swellable polymer and an osmotic inducing agent. The squeeze-type of claim 1, wherein the pharmaceutical composition and the squeeze expansion layer further comprise one or more additives selected from the group consisting of binders, swelling aids, lubricants, surfactants, dispersants, wetting agents, and dyes. Osmotic drug delivery device. 15. The squeeze-type osmotic drug delivery device according to claim 1 or 14, wherein the osmotic inducing agent is selected from the group consisting of salts, sugars, ureas and tartaric acid. 15. The squeeze-type osmotic drug delivery device according to claim 1 or 14, wherein the amount of osmotic agent in the squeeze expansion layer is 1.0 to 50% by weight relative to the total amount of the pharmaceutical composition layer and the squeeze expansion layer. 15. The squeeze-type osmotic drug delivery device according to claim 1 or 14, wherein the amount of the osmotic inducing agent in the pharmaceutical composition is 1.0 to 50% by weight relative to the total amount of the pharmaceutical composition layer and the squeeze expansion layer. The osmotic drug delivery device according to claim 16, wherein the salt is selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium chloride and calcium bicarbonate. The squeeze type osmotic drug delivery device according to claim 16, wherein the saccharide comprises one or more sugars selected from the group consisting of mannitol, glucose, lactose, sucrose, and mixtures thereof. The method according to claim 1 or 14, wherein the swellable polymer is polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyacrylate, polymethacrylate, gelatin, polyethylene oxide Squeeze-type osmotic drug delivery device, which is at least one component selected from the group consisting of polyvinyl pyrrolidone and mixtures thereof. 15. The squeeze-type osmotic drug delivery device according to claim 1 or 14, wherein the amount of swellable polymer in the squeeze expansion layer is 10 to 80% by weight based on the total amount of the pharmaceutical composition layer and the squeeze expansion layer. 15. The squeeze-type osmotic drug delivery device according to claim 1 or 14, wherein the amount of the swellable polymer in the pharmaceutical composition is 1 to 50% by weight based on the total amount of the pharmaceutical composition layer and the squeeze expansion layer.