JPH07508735A - Drug delivery device and method for manufacturing the device - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Drug delivery device and method of manufacturing same The present invention delivers drugs to the colon for and contained within the polymer matrix and the matrix or A drug delivery device comprising a drug encased by a matrix.

Many drugs are highly sensitive to proteolytic enzymes found in the digestive fluids of the stomach and small intestine. Sensitive. Pharmaceuticals such as peptides and proteins are processed by proteolytic enzymes. decomposes, thus substantially reducing its absorption.

Oral administration is relatively convenient and is easily accepted by patients. The most common method of delivery of pharmaceuticals such as proteins is by parenteral administration.

Previous studies have shown that the concentration of proteolytic enzymes in colonic fluid is lower than that of gastric and small intestinal fluids. It has been shown that it is much lower than the a degree in

Therefore, to selectively administer drugs to the large intestine by administering them through the gastrointestinal tract. It would be extremely beneficial if we could find a suitable technique for this.

Polymeric materials such as hydrogels are widely used in pharmaceutical carrier systems for controlled release. , or is conventionally used as a device that responds sharply to stimuli. like that Devices are, for example, "hydrogels in medicine and pharmacy" (Hydrogels in medicine and pharmacy). els inMedicine and Pharmacy-), N, A , Peppas (M7i), CRC Press, +987 has been done. The combination drugs described therein are generally not biodegradable. That kind of game The release of a pharmaceutically active ingredient loaded into a gel usually depends on the water content in the gel. dominated by mere diffusion within the dependent device. Therefore, these gels can be administered orally. There are no indications for drug delivery to specific areas of the intestine after administration.

European Patent Application No. 357 401 describes proteins, polysaccharides and cross-linking agents. A biodegradable hydrogel matrix is disclosed. However, this composition The product is not used for oral administration.

U.S. Pat. No. 4,024,073 discloses a chelating agent attached to a polymer chain. water-soluble polymers, and the ability to cross-link polymer molecules through chelating agents. It describes the production of compressed tablets for delivery. Are all of these conventionally time-dependent? The active ingredient is contained in the center covered by a coating consisting of: This coach patents that are susceptible to population changes during the intestinal transit time and that contain active substances in the colon. A system is described that does not release at a constant rate.

An osmotic drug device for delivering drugs to the colon is disclosed in UK Patent Application No. 216605 No. 1 and No. 2 168 052. These devices are drugs It consists of a laminated membrane surrounding a compartment containing. The membrane has a time delay before the substantial release of the drug begins. result. Such an osmotic drug device is described in UK patent application no. It suffers from the same drawbacks as the device described in No. 066.070.

Publications related to the field of the invention include: Enzymatically Controlled Oral Drug Delivery 7 Chemically-modified polysaccharide J accharides for this system takes advantage of the presence of amylase in the small intestine and therefore is not targeted for release into the large intestine or colon.

Recently, Rubinstein et al. (Pharm, Res., 9. 276-2 78. (1992) demonstrated the delivery of colonic drugs through the use of chondroitin matrices. reported. The system is embedded within a compressed matrix of chondroitin. It consists of drugs. This matrix can disintegrate at any time during passage through the small intestine. can. Therefore, this system is not suitable for site-specific drug delivery to the colon.

International Patent Application No. 92100732 discloses oral delivery of therapeutically active substances to the colon. It describes a composition for use in This composition consists of the active substance (single amount) dispersed therein. a matrix core with a number or more) and an envelope without any active substance Consists of layers. Both the matrix core and the envelope layer are The cations are divalent or trivalent) to form coacervates. They are based on polysaccharides such as esters and/or dextran.

In the stomach of patients with normal gastric acid function, hydrogen ions are absorbed into the outer layer and core of the composition. hydrogen ions to polyvalent cations by ion exchange. on, leaving the polysaccharide chain largely uncomplexed and more or less positive. The compositions will be held together by steric effects rather than ionic bonds.

This means that the composition is broken down to some extent during its passage through the small intestine, and Decomposition during this passage may be affected by the presence of other cations, the residence time of the composition and especially This means that it is extremely dependent on the person's stomach acid function. In other words, the composition of the above type a patient's outcome if the composition is made specifically for that patient. It may be possible to deliver active substances to the intestine. Therefore such a composition Not commercially suitable.

The use of hydrogels containing biodegradable bonds has been described by Brφndsted and Kopece. Proceed, Intern, Symp, Control, by k Re1. Bioact, Mater, ±8,345-346°! to 991 Already mentioned. Hydrogels are pH sensitive due to acidic groups incorporated into the polymer backbone. exhibits dependent swelling and is also biodegradable due to enzymatically labile crosslinking. vinegar. This system takes advantage of the presence of microbial abreductase in the colon.

These hydrogels degrade after crosslinking collapse and release of the polymer backbone.

By using these acidic hydrogels, any drug production in the stomach can be avoided. Qualitative degradation and release can also be avoided. However, hydrogel degradation and Therefore, the release of drug into the colon appears to be very slow, and Only a portion of the drug may be released when the drug is released.

Drug delivery to the colon was achieved by using dextran prodrugs (Larsenetal, Pm "aLRes,, 6.995- 999. 1989).

The prodrug is the active substance after cleavage by microbial enzymes present only in the colon. It emits. The drug was co-bound to dextran. prodrug When the dextran reaches the colon, bacterial dextranase destroys the dextran and binds it covalently. The drug was released after hydrolysis. The drawback of this system is the severe drug loading problem. It's in the title. Furthermore, the drug must possess suitable functional groups for modification. , and the experimental conditions for coupling with the dextran carrier (; Must be.

Therefore, a need exists for an oral drug delivery device with improved selectivity to the colon. It is clear that

It is an object of the present invention to provide such an oral drug delivery device for delivering drugs to the colon. use of such devices to administer one or more drugs. Delivery to the colon, stomach, small intestine, and stool without substantial drug loss It is possible.

A drug delivery device according to the invention comprises a polymer matrix and a polymer matrix thereof. consisting of a drug contained within or encapsulated by the polymer matrix; Trix is a network between dextranase-degradable polymers and their polymer chains. It is a cross-linked hydrogel with coexisting bonds consisting of a cross-linking agent that provides eye-like bonds. It is characterized by

As mentioned above, dextranase is only present in the colon. Drug delivery according to the invention In the device, the drug was cross-linked as the device passed through the stomach and small intestine. Protected by a dextranase-degradable polymer. Once it reaches the colon, poly The mer matrix is degraded by dextranase to release the drug.

The rate of degradation of the polymer matrix and thereby release of drug depends on several factors, For example, the selection of dextranase-degradable polymers, crosslinking agents, degree of crosslinking, It depends on the water content of the drogel matrix and the shape and size of the finished device. Exists. The device according to the invention is such that substantially all of the drug is released in the colon. can be configured.

The dextranase-degradable polymer in the device according to the invention is It must be inherently resistant to digestive fluids.

Preferably, the dextranase-degradable polymer is dextran or modified dextran. It's Tran. Several methods are known for transforming dextran. example For example, W. M. Mecker for the production of diethylaminoethyl dextran. nan & C,R.

0-426.1972.

By using modified dextran instead of regular dextran, it becomes more hydrophobic. It is possible to obtain hydrogels that have a more hydrophilic or more hydrophilic as well as naturally imposed properties. I can do it. This is used to suppress the swelling properties of the hydrogel matrix. can be done. Dextranase-degradable polymers are also hydrogel matrices Dextranase-degradable The polymer will not react with the drug in a way that would inversely inactivate the drug. cormorant.

In particular, sulfate esters (hyalkoxyl fIS, oxidized or esterified dextrin Strang is preferred.

Dextranase degradable polymers are 10,000 and 2,000,000g/mol molecular weight between 40,000 and 2,000,000 g mol can have.

70,000 if the dextranase-degraded polymer is dextran. and 500.000 are optimal.

A crosslinking agent is a non-toxic agent that can provide a network-like polymer structure. Good too. The polymer has coexisting bonds, such as urethanes, esters, ethers, Can be linked by a mido, carbonate, or carbamate linkage . Diisocyanates that provide urethane bonds, e.g. hexamethylene diisocyanate and 1. 4-phenylene diisocyanate is particularly preferred as a crosslinking agent. Yes.

The cross-linking rate of the hydrogel is determined by the degradation of the matrix as well as the composition of the hydrogel itself. Affects speed, loading, and overall release profile. In other words, the bridging rate is The higher the rate will generally result in slower degradation and release, and the higher the Lower values will result in faster degradation and release.

Of course, the effect that cross-linking rate has on drug release is influenced by the size of the drug molecule and the drug depending on how the device is filled. Preferably, the crosslinking agent is within the hydrogel. constitutes 0.05-25 mol% of monomer units.

The drug can in principle be any type of drug. Device according to the present invention In particular, drugs for the treatment of diseases of the colon, such as steroids, 5-aminosalicyl Used when administering acids, anti-inflammatory drugs, anti-cancer drugs, enzymes, and cultured bacteria. or drugs that are unstable in the stomach and/or small intestine, e.g. and vaccines.

Devices according to the invention are also useful for use in time-delayed administration of drugs. Ru.

The use of the device of the invention allows for example Medications, such as pain medication, can be administered to a patient at bedtime, causing the device to reach the colon. It takes about 8 hours, so you can see the effects in the morning.

Drugs can be loaded into hydrogels in several ways. For example, drugs, gelatin capsules containing drugs or drugs are covered by a hydrogel matrix. or the drug can be contained within the lumen of the hydrogel device. (i.e., the drug can be surrounded by a thick layer of vitrogel matrix).

Methods of incorporating drugs into hydrogels are well known to those skilled in the art and include, for example, S, W.

Kimetal, Pharm, Res, 9. 283-290. 19 92.

In a preferred embodiment of the device according to the invention, the drug is a cross-linked hydrogel. uniformly distributed within the matrix.

Depending on how the drug is loaded, hydrogel matrices can be used as capsules, tablets, etc. It can be made into shapes such as sheets, films, and microspheres. hydrogelmato Compositions formulated using Rix can be prepared using conventional pharmaceutical carriers, additives, adjuvants, etc. can include.

Devices according to the invention can contain more than one type of drug. for example , the device injects one high molecular weight drug into the lumen of the hydrogel matrix and one of the ponds. A species of low molecular weight drug can be included uniformly dispersed within the matrix.

It is of course possible that other combinations of drugs released in the stomach or small intestine are possible. This should be obvious to entrepreneurs.

Another object of the invention is to provide a method for manufacturing a drug delivery device according to the invention. It is to provide.

The method according to the invention comprises: a) dissolving a dextranase-degradable polymer in a solvent, b) said polymer adding a cross-linking agent capable of covalently cross-linking - to the solution; C) reacting the cross-linking agent with a dextranase-degradable polymer to form a cross-linked providing a drogel matrix; Consists of.

There are several ways to load the drug into the device before the cross-linking reaction is complete. It is possible. These methods are also well known to those skilled in the art and include, for example, S, Z .

Songetal, J. Pharm, Sci., 70. 216-21 9. It is described in 1981.

In a preferred embodiment, the drug is deactivated by the next step after the trickling reaction is completed. Filled in the chair.

a) Pre-dry the hydrogel matrix to preferably contain up to 30% by weight of In particular, the water content should be 10% by weight or less.

b) contacting the dried drogel matrix with a liquid drug or a solution of the drug; swell.

C) If desired, dry the hydrogel. This last method allows the drug to be homogeneous. A very simple and convenient method for manufacturing the device according to the claimed invention, which is Provide an easy way.

A series of further examples are provided to illustrate the invention.

Figure 1 is a graph showing the equilibrium swelling degree of the device according to the invention depending on the DMSO content. It is f.

Figure 2 shows a graph showing the equilibrium swelling degree of the device according to the invention depending on the crosslinking agent content. It's rough.

Figure 3 shows the equilibrium swelling degree of the device according to the invention depending on the molecular weight of dextran. This is a graph.

Figure 4 shows the time-dependent effects of the device according to the invention in the cecum and stomach, respectively. FIG.

Figure 5 shows the release profile of hydrocortisone from the device according to the invention. .

8.000 (commercially available from Pharmacia). 5ml (85 % by volume) in anhydrous dimethyl sulfoxide (DMSO). Dextran As soon as it dissolves into a clear, slightly viscous solution, 86 μI (0.46 mmol) ~5 mol %) of hexamethylene diisocyanate (HDL crosslinking agent) was added.

This was done in a completely dry glass pot, which indicates that this cross-linking reaction This is because it is obstructed by water. For film production, pour the solution into the film using a syringe and needle. Transferred to a reaction mold. The mold is Teflon coated with two water cooling jackets. It consisted of aluminum blocks, between which the solution was placed. vinegar By adjusting the spacing of those blocks using a pacer ring, The thickness of the resulting hydrogel film can be controlled. Adjust the temperature to 70℃ I arranged it. The crosslinking reaction was carried out at this temperature for 24 hours.

In a similar manner, dextran 70 and various amounts of HDI and DMSO were included. Four other hydrogels were synthesized. The two gels contained 2.5 and 10 mol% HDI. , and 2 fl contained 80 and 90% DMSO by volume.

The molecular weight of the dextran was also varied. Dextran 1 hydrogel 0.500 and 2000 (respective molecular weights 10,000.500,000 and 2 Made with ゜000.000).

Table 1 shows a summary of the synthesized hydrogels.

Table 1 A 70000 85 2.5 B 70000 85 5 C700008510 D 70000 80 10 E 70000 90 10 F 500000 85 5 G 2000000 85 5 Volume % is calculated on the volume of reaction mixture produced. Mol% is used Calculated based on the molar content of glucose in the amount of dextran added.

Hydrogel prepared in Example 1 of measurement of equilibrium swelling degree of biodegradable hydrogel The equilibrium swelling degree of samples A-G was studied.

Cut out three disks from each sample and calculate the weight of the swollen gel in water and DMSO. It was measured. The gels were washed with water and then incubated at room temperature for 2 days and in vacuo for 40 days. It was dried at 50°C for 2 days. Equilibrium swelling is the mass of the swollen gel equal to that of the dry gel. It was evaluated as a ratio to that of

Figure 1 shows the equilibrium swelling of hydrogels containing various amounts of DMSO in the reaction mixture. The dependencies are illustrated.

Increasing the amount of DMSO in the reaction mixture results in an increase in the equilibrium swelling of the resulting hydrogel. bring about fruit. This is more pronounced in DMSO than in water.

Figure 2 shows that the equilibrium swelling degree decreases as the cross-linking density of the hydrogel increases. shows.

From Figure 3, it can be seen that if the molecular weight of dextran is changed, it will affect the equilibrium swelling degree substantially. It is possible to see that there is no effect on the person.

The equilibrium degree of swelling is greater in DMSO than in water. Therefore, DMSO This appears to be a good example of a viable vehicle for loading drugs into drogels. Ru.

The lanase units (kDU/g) were used in the study. Hydrogel film disc, diameter 5 pieces and 1.6 m thick, prepared as described in Example 1 and cut out. Swelling was performed with 1M acetate buffer pH 5.4 until equilibrium was reached. Swelling equilibrium is achieved After washing the discs with 1 ml of O, 1M acetate buffer pH 5.4 and 0.5.3 or 12 Transferred to an enzyme mixture consisting of μl of dextranase. The mixture in a water bath for 3 Incubate at 7°C and record the time required for complete dissolution of the disc. Ta. Gel degradation was tracked by the decrease in thickness.

Table 2 shows that the enzyme mixture consisted of 12 μl dextranase/ml buffer. τ for various gels of mushrooms are shown. As the bridging density increases, τ becomes increases and thus degradability decreases. This also relates to the degree of equilibrium swelling. degree of swelling The higher the value, the higher the degradability of the hydrogel. However, these results also reflect the structural factor is also shown to affect the degradability of the vitrogel.

Table 3 shows that as the amount of dextranase increases, the degradation rate increases. .

B 36±4.6 C60±4.9 D255±15 G 33±0.6 Table 3 Sample Amount of dextranase (μm) τ (min) B O, 5157 ± 5.3 B 3 131±14.8 B 12 36±4.6 After weighing six 5 m diameter disc samples of B hydrogel, the discs were Preswelled in H7,4 potassium phosphate isotonic buffer. Place each disc in a gauze bag I put it inside. Put those gauze bags into the stomach of a male SD rat (20G-300g). After implantation into the cecum, the gel was firmly fixed to the intestinal wall to prevent expulsion. La The kittens were then allowed access to water and food ad libitum. At various times (l, 2o) On days 1 and 3), the rats were sacrificed and the gel was collected. The gels in DMSO and water I washed it and then dried it. Record the dry weight, and calculate the gel degradation as % degraded (dry The weight loss was evaluated as a percentage of the initial dry weight. initial dry weight The amount was between 42 and 45 mg.

Figure 4 shows that after 3 days, the gel transplanted into the cecum was degraded, and the gel transplanted into the stomach was separated. Indicate that you did not understand. This is because gel decomposition occurs in vivo, and this indicates that it occurs in the cecum and not in the stomach.

Example 5 Hydrocortisone loading and in vitro release prepared as described in Example 1. Made with a diameter of 1. 5mm and thickness 1. 6nn hydrogel disk (sample B ) was washed in water and then dried. After drying, the disc was treated with hydrocortisone DM. It was immersed in a drug solution (72.5 mg/ml) in SO. Add the same amount of gel at 24 hours. Dry in air at 50"C for 2 days. Release of hydrocortisone from the disc was 0.1 ! 4 in salt buffer pH 5.4 (24 μl dextranase/ml buffer) studied with and without the presence of dextranase. Release 5ml of gel It was immersed in the medium and kept at 37°C in a water bath. 8 minutes if enzyme is present Take 2.5 ml samples at intervals and at 30 minute intervals if no enzyme is present. and replaced with fresh medium. The amount of hydrocortisone released is determined by reverse-phase HP Methanol:water 60:40,242 as mobile phase on C-18 column by LC UV detection in an and an injection volume of 20 μl was determined.

After 30 minutes, 0.72 mg of hydrocortisone was added to the gel soaked in the enzyme-containing buffer. compared to 0.11μ from the gel in pure buffer. Ta. This indicates that release was dramatically increased by the presence of dextranase. vinegar.

Figure 5 shows the release profile of hydrocortisone from the hydrogel. Dexto Hydrocortisol release is much more rapid when lanase is present in the release medium. The emission of light has been obtained.

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Claims (12)

[Claims] 1. Polymer matrices and In a drug delivery device consisting of a drug wrapped in a polymer matrix, Lix is shared between dextranase-degradable polymers and their polymer chains A cross-linked hydrogel mate comprising a cross-linking agent that provides a network-like bond through bonding. The drug delivery device as described above, characterized in that it is a drug. 2. The dextranase-degradable polymer is dextran. A drug delivery device according to claim 1. 3. The dextran is not sulfated, alkoxylated, oxidized or esterified. The drug delivery device according to claim 2, characterized in that: 4. The dextranase-degradable polymer has 10,000 and 2,000,000 g/mol, preferably between 40,000 and 2,000,000 g/mol , and in particular have a molecular weight of between 70,000 and 500,000 g/mol. The drug delivery device according to any one of claims 1 to 3, characterized in that: 5. Claims 1 to 4, wherein the crosslinking agent is a urethane bond forming agent. The drug delivery device according to any one of . 6. The urethane bond forming agent is hexamethylene diisocyanate or 1,4-phenylene The drug delivery device according to claim 5, characterized in that it is nylene diisocyanate. chair. 7. The crosslinking agent constitutes 0.05-25 mol% monomer units in the hydrogel. The drug delivery device according to any one of claims 1 to 6, characterized in that: chair. 8. characterized in that the drug is uniformly dispersed within the hydrogel matrix. The drug delivery device according to any one of claims 1 to 7. 9. From claim 1, wherein the drug is encapsulated by the matrix. 7. The drug delivery device according to any one of items 7 to 7. 10. A method of manufacturing a drug delivery device, the method comprising: a) dextrana; b) dissolving the enzyme-degradable polymer in a solvent; b) covalently linking the polymer; c) adding a cross-linking agent that can be A cross-linked hydrogel matrix is produced by reacting with a degradable polymer to create a drug The material is placed in the solution before the reaction between the polymer and the crosslinking agent is completed. manufacturing a drug delivery device comprising: how to. 11. Before the cross-linking reaction between the drug and the polymer and cross-linking agent is completed. according to claim 10, characterized in that the cross-linking reaction is completed after Method. 12. A solution or liquid drug of the drug is added to a pre-dried hydrogel. A claim characterized in that it is filled into a cross-linked hydrogel by absorption. The method according to claim 10.