HUT75665A - A drug delivery device and a method of making such device - Google Patents

Abstract

A drug delivery device comprising a polymer matrix and a drug contained in or surrounded by the matrix which polymer matrix is a cross-linked hydrogel matrix comprising a dextranase degradable polymer and a cross-linking agent providing covalent bonded network linkage between the polymer chains. The device is suitable for delivering drug to the colon. A method of making the device comprising: (a) dissolving a dextranase degradable polymer in a solvent; (b) adding a cross linking agent capable of cross-linking the polymer with covalent bonds to the solution; (c) allowing the cross-linking agent to react with the dextranase degradable polymer to provide a cross-linked hydrogel matrix, and loading the drug into said solution before or after the reaction between the polymer and the cross-linking agent has finished.

Description

For the manufacture of a device and method for delivering a therapeutically active agent

ASTRA AB, Södertálje, SE

inventors:

BRONDSTED Helle, Farum, DK

HOVGAARD Lars, Farum, DK

Date of filing: 06/07/1993

Priority: 07.07.1992 (0895/92) DK

International Application Number: PCT / DK93 / 00227 International Publication Number: WO 94/01136

80905-4601 / TEL

The present invention relates to drug delivery devices which deliver drugs to the colon and which comprise a polymeric matrix and a matrix containing or surrounding the drug.

Most drugs are highly sensitive to protein-degrading enzymes in the digestive juices of the stomach and small intestine. Medicines, such as peptides and proteins, are degraded by protein-degrading enzymes and thus substantially reduce their absorption.

Although oral administration is much more convenient and acceptable for patients, parenteral administration is the most traditional route of administration of peptides and protein delivery drugs.

Research has shown that protein-degrading enzymes are present in colon juices at much lower concentrations than in gastric and small intestine juices.

Accordingly, it would be highly advantageous to develop an appropriate technique for delivering drugs that would selectively deliver the drugs to the colon, even when administered via the gastrointestinal tract.

Polymeric substances, such as hydrogels, are widely used in drug delivery systems for controlled release systems or are used as devices sensitive to external influences. Such devices are described, for example, in Hydrogels in Medicine and Pharmacy, N.A. Peppas, CRC Press (1987). These formulations are generally non-biodegradable (non-biodegradable). The release of pharmaceutically active agents loaded into such gels is usually controlled by simple diffusion in the device, which depends on the water content of the gel. Therefore, these gels are not suitable for delivering the drug to specific parts of the intestinal tract after oral administration.

EP 357 401 discloses a biodegradable (biodegradable) hydrogel matrix comprising a matrix protein, a polysaccharide and a crosslinking agent. This product is not intended for oral administration.

US 4,024,073 discloses a water-soluble polymer hydrogel composition comprising a polymer chain-linked chelating agent and a polyvalent metal ion that crosslinks polymer molecules through a chelating agent. The hydrogel may be used as a carrier for the sustained release of drugs and medications, however, it is not mentioned herein that the target of these formulations is the large intestine.

JP 1 156 912, JP 62 010 012, JP 5 721 315, DE 3 400 106 and US 4 496 553 disclose the preparation of slow release tablets using soluble polymers or polysaccharides. These are all conventional tablets that are disintegrated in a time-dependent manner and are not specifically targeted to the large intestine.

GB 2,066,070 discloses a tablet formulation which delivers the active ingredient in the colon. This tablet contains the active ingredient in the center of a tablet coated with cellulose and cellulose derivatives. The coating is broken down by bacteria present in the colon. The disadvantage of this system is that the coating may dissolve in the stomach or upper gastrointestinal tract. The disadvantage of the system is that due to differences between individuals the residence time in the intestinal tract is different and thus the system releases the active ingredient non-specifically in the colon.

GB 2,166,051 and 2,166,052 disclose osmotic drug delivery devices for administration of drugs to the colon. These devices consist of a laminated membrane that surrounds the drug-containing compartment. Due to the membrane, the onset of the actual release of the drug is shifted over time. Such osmotic drug delivery devices have the disadvantages described in GB 2,066,070.

The subject matter of the present invention is the chemically modified polysaccharides for enzymatically-controlled hourly drug delivery published by Kost et al., Biomaterials, 11, 695-698 (1990). This article describes a system in which ionically cross-linked starch is used to regulate the release of poppy5 romolecules in the intestine. The system is degraded by the small intestine amylases and is thus not intended to release the colon or column.

Today, Rubinstein et al., Pharm. 9: 276-278 (1992) describes a drug delivery system on a cola using a chondroitin matrix. The system consists of a drug embedded in a chondroitin press matrix. This matrix may also disintegrate during passage through the small intestine. As such, this system is not suitable as a site-specific drug delivery system for the column.

International Patent Publication No. WO 92/00732 discloses a composition which delivers the drug to the column by oral administration. The composition consists of a matrix core in which the active ingredient or agents are dispersed and an outer layer without any active ingredient. Both the matrix core and the outer coating layer are based on polysaccharides such as pectin and / or dextran, which form a coacervate through polyvalent cationic crosslinking agents, where the cation is divalent or trivalent.

In the stomach of patients with normal stomach acid, the hydrogen ions are infiltrated into both the outer layer and the nucleus of the composition, and by ion exchange, the hydrogen ions replace the polyvalent cations, thereby leaving the polysaccharide chains in a instead of binding, they are spherical effects.

This means that the preparation is more or less disintegrated during passage through the stomach and small intestine, which disintegration is highly dependent on the presence of other cations, the residence time of the preparation and, in particular, the gastric acid function of the patient. In other words, such formulations are capable of delivering the active agent to the patient's column if the formulation is specifically formulated for the particular patient. As such, these compositions are not commercially available.

The use of hydrogels with biodegradable linkages is described in Brondsted and Kopecek, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18, 345-346 (1991). Thanks to the acidic groups incorporated in the polymer backbone, the hydrogels have a pH-dependent swell, while they are biodegradable due to enzymatically labile cross-links. The system utilizes microbial azoreductases present in the column. Hydrogels disintegrate after crosslinking and release of the polymer backbone.

The use of these acidic hydrogels avoids degradation and drug release in the stomach. However, it is disadvantageous that the degradation, degradation and thus release of the drug in the column by the hydrogel is very slow and thus only a fraction of the drug may be released during passage through the column.

Larsen et al., Pharm. Gap. 995-999 (1989) describes the preparation of a drug delivery system that delivers the drug to the column. The system is obtained using dextran prodrugs, which release the active ingredient only after cleavage by microbiological enzymes present in the column. The drug is covalently bound to dextran. As soon as the prodrug reaches the column, the dextran is degraded by bacterial dextranases and the drug is released after hydrolysis of the covalent bonds. The disadvantage of this system is that it is very difficult to incorporate the drug. The drug must have appropriate functional groups for modification and also have to withstand experimental conditions for association with dextran carrier.

In view of the foregoing, it is obvious that an oral drug delivery device is required which delivers the drug to the column with better selectivity than hitherto.

It is an object of the present invention to provide an oral drug delivery device that delivers a drug to the column and which allows one or more drugs to be specifically delivered to the column without loss of drug in the stomach, small intestine, or drug. with feces.

The drug delivery device of the present invention consists of a polymer matrix and a drug which is contained within or surrounded by the polymer matrix. The polymer matrix is a hydrogel matrix cross-linked by covalent cross-linking, which consists of a botnium polymer under the influence of dextranases and a cross-linking agent for crosslinking polymer chains.

As mentioned above, dextranases are present only in the column. In the drug delivery device of the present invention, the drug is protected by a crosslinked dextranase degradable polymer while passing through the stomach and small intestine. As the device reaches the column, the polymer matrix is degraded by dextranase and the drug is released. The rate of polymer degradation and thus drug release rate depends on many factors such as the type of polymer that is degraded to dextranase, the crosslinking agent, the degree of crosslinking, the water content of the hydrogel matrix and the configuration of the final device. The device of the invention may also be designed to release virtually all drugs in the column.

The dextranase degradable polymer used to form the device of the present invention should be substantially resistant to gastrointestinal fluids in the stomach and small intestine.

Preferably, the dextranase degradable polymer is dextran or modified dextran. There are several methods known for modifying dextran. For example, the preparation of diethylaminoethyl dextran is described in W.M. Meckernan and C.R. Ricketts, Biochem. J. 76, 117-120 (1960); and the preparation of dextran sulfate are described in K.

»· · · · ·

Nagasawa et al., Carbohydr. Gap. 21, 420-426 (1972).

By using a modifying dextran instead of dextran, it becomes possible to obtain a more hydrophobic or hydrophilic or charged hydrogel matrix. This can be used to control the swelling properties of the hydrogel matrix. The choice of dextranase-degradable polymer should also take into account what drug is to be embedded in the hydrogel matrix. The dextranase-degradable polymer should be selected in such a way that it does not react with the drug and thus does not irreversibly alter its activity. Sulfatase, alkoxylase, oxidase or esterified dextran are particularly preferred.

The dextranase-degradable polymer has a molecular weight of from 10,000 to 2,000,000 g / mol, preferably from 40,000 to 2,000,000 g / mol. In the case where the dextranase-degradable polymer is dextran, it preferably has a molecular weight of 70,000 to 500,000 g / mol.

The crosslinking agent may be a non-toxic agent capable of providing crosslinking of the polymer structure. The polymers may be linked by covalent bonds such as urethane, ester, ether, amide, carbonate or carbamate bonds. Diisocyanates can be used to form urethane bonds. Preferred examples of such crosslinking agents are hexamethylene diisocyanate and 1,4-phenylene diisocyanate.

The degree of crosslinking of the hydrogel, just like the composition of the hydrogel, influences the degradation kinetics, loadability and degradation profile of the matrix as a whole. This means that the higher the degree of crosslinking, the greater the degree of crosslinking. slower matrix degradation and drug release, and the lower the degree of crosslinking, the faster the degradation and release.

Of course, the effect of the degree of crosslinking on the drug release depends on the molecular size of the drug as well as the manner in which the drug is inserted into the device. Preferably, the crosslinking agent forms from 0.05 to 25 mol% monomer units in the hydrogel.

In principle, the drug can be any type of drug. The device according to the invention is particularly suitable for the administration of medicaments for the treatment of diseases of the colon, such as steroids, 5-amino-salicylic acid, anti-inflammatory agents, anticancer agents, enzymatic agents and bacterial cultures. The device of the invention is also useful for the administration of drugs which are unstable in the stomach and / or small intestine, such as peptides, including insulin, vasopressin or growth hormones, proteins, enzymes and vaccines.

The device of the invention is also useful for the administration of time delayed drugs.

When the device of the invention is used to deliver drugs or other analgesics for treating rheumatism, for example, the device can be administered to the patient at bedtime and thus the drug is effective in the morning as it takes 8 hours for the device to touch.

The drug can be incorporated into the hydrogel matrix in a number of ways. For example, the drug or drug-containing gelatin capsule may be coated with a hydrogel matrix, or the drug may be contained within the hydrogel device, i.e., the drug may be surrounded by a thin layer of a hydrogel matrix.

The incorporation of drugs into a hydrogel is within the skill of those of skill in the art, for example, such a method of injection is described in S.W. Kim et al., Pharm. Gap.

9: 283-290 (1992).

In a preferred embodiment of the device according to the invention, the drug is homogeneously dispersed in the crosslinked hydrogel matrix.

Depending on the mode of drug delivery, the hydrogel matrices may be in the form of capsules, tablets, films or microspheres. Formulations using hydrogel matrices may also contain conventional pharmaceutical carriers or vehicles, adjuvants, and other excipients.

The device of the present invention may contain more than one drug, for example, the device may comprise a high molecular weight drug within the hydrogel matrix and another lower molecular weight drug dispersed homogeneously in the hydrogel matrix.

It will be apparent to those skilled in the art that other combinations may be contemplated, such as those containing drugs that are upset in the stomach or small intestine.

The invention further relates to a method of forming a device according to the invention. In the process of the invention

a) dissolving the dextran degradable polymer in a solvent,

b) adding to the solution a curing agent capable of crosslinking the polymer with covalent bonds,

c) then allowing the crosslinking agent to react with the dextranase degradable polymer to thereby form a crosslinked hydrogel matrix.

The drug may be inserted into the device before the crosslinking reaction is complete. There are many conventional methods known to those skilled in the art, such as S.Z. Song et al., J. Pharm. Sci., 70, 216-219 (1981).

In a preferred embodiment, the drug is inserted into the device after the crosslinking reaction is complete. During the procedure

a) pre-drying the hydrogel matrix, preferably to a water content of less than 30% by weight, more preferably less than 10% by weight,

b) contacting the dehydrated hydrogel matrix with the liquid drug or drug solution and allowing it to swell,

c) drying the hydrogel, if desired.

The latter method is a very simple and easy way of making the device according to the invention, which results in a device in which the drug is homogeneously dispersed in boiling water.

The invention is illustrated in detail by the following examples.

Description of diagrams

Figure 1

The figure shows the equilibrium degree of swelling (weight of swollen gel relative to dry gel weight) of the device of the invention as a function of DMSO content.

Figure 2

The figure shows the equilibrium degree of swelling (weight of swollen gel relative to dry gel weight) of the device of the present invention as a function of the amount of crosslinking agent.

Figure 3

The figure shows the equilibrium degree of swelling (weight of swollen gel relative to dry gel) of the device of the invention as a function of the molecular weight of dextran.

Figure 4

The figure shows the decomposition of the device of the invention in the caecum over time.

Figure 5

The figure shows the release profile of hydrocortisone from the device of the invention.

Example 1

Preparation of Biodegradable Dextran Hydrogels

Dextran 70 (molecular weight: 70,000, commercially available from Pharmacia) (1.5 g, 9.25 mmol glucose unit) was dissolved in 8.5 mL (85 volumes) of anhydrous dimethyl sulfoxide (DMSO) immediately after the dextran was pure. , dissolves into a low viscosity solution. To the solution was added 86 μπι (0.46 mmol, about 5 mol%) hexamethylene diisocyanate (HDI, crosslinker). All these steps are carried out in a well-dried glass flask, since the crosslinking reaction is prevented by water traces.

The solution is then placed in a mold using a needle and syringe to make the film. The mold consists of two Teflon-coated aluminum blocks with a water jacket, between which the solution is placed. By using a spacer ring, the spacing between the blocks can be adjusted, thereby allowing the thickness of the hydrogel film to be controlled. The temperature is adjusted to 70 ° C. At this temperature, the crosslinking reaction takes place within 24 hours.

Similarly, four other hydrogels are prepared which are dextran 70 hydrogels and varying amounts of HDI and • · · «· ·« ···

They contain DMSO. Two gels contain 2.5 and 10 moles * HDI and two other gels contain 80 and 90 volumes * DMSO.

The molecular weight of dextran was also changed. Hydrogels were prepared from dextran 10, 500 and 2000 (molecular weights 10,000, 500,000 and 2,000,000).

The composition of the synthesized hydrogels is shown in Table 1.

Table 1

Sample Dextran DMSO HDI (Molecular Weight) (v / v) (mol%)

THE 70,000 85 2.5 B 70,000 85 5 C 70,000 85 10 D 70,000 80 10 E 70,000 90 10 F 500,000 85 5 G 2,000,000 85 5 Volume * values the received reaction volume calculated. . The mole * values of employee

calculated based on the molar glucose content in dextran.

- 16 • * »« ·. example

Determination of the degree of swelling equilibrium of biodegradable dextran hydrogels

The l. Examples A-G were used to determine the degree of swelling equilibrium of the hydrogels prepared in Example 1A. Three plates of each hydrogel were excised and the weight of the gel swelled in water and DMSO was measured. The gels were washed with water and then dried at room temperature for 2 days and then in vacuo at 40-50 ° C for 2 days. The degree of swelling equilibrium is expressed as the weight ratio of swollen gel to dry gel.

Figure 1 shows the degree of equilibrium swelling of hydrogels made from a mixture of different amounts of DMSO in the reaction mixture in water and DMSO. Increasing the amount of DMSO in the reaction mixture results in increasing the degree of swelling equilibrium of the hydrogel formed. This is much more obvious in DMSO than in water.

Figure 2 clearly shows that increasing the density of hydrogel crosslinking bonds reduces the equilibrium degree of swelling.

It is clear from Figure 3 that changing the molecular weight of dextran does not substantially affect the equilibrium degree of swelling.

The degree of swelling equilibrium in DMSO is greater than in water. Thus, DMSO can be considered as a suitable vehicle for incorporation of drugs into hydrogels.

Example 3

In vitro degradability study of hydrogels

In vitro degradation of hydrogels was investigated using dextranase (50 kilo dextranase units / g). The l. Plates of 5 mm diameter and 1.6 mm thickness were excised from the hydrogel films described in Example 1A and allowed to swell in 0.1 M acetate buffer, pH 5.4. Once the swelling equilibrium was reached, the plates were placed in the enzyme mixture containing 1 ml of 0.1 M acetate buffer (pH 5.4) and 0.5 μΐ, 3 μΐ or 12 μΐ dextranase. The mixture was incubated in a water bath at 37 ° C and the time required for complete dissolution of the plates (τ) was recorded.

The degradation of the gels was followed by a decrease in thickness.

Table 2 shows the τ values for the various gels in the 12 μΐ dextranase / ml buffer enzyme mixture. As the degree of crosslinking increases, so does τ, and thus the degradability decreases. This is also related to the degree of swelling equilibrium, i.e. the higher the degree of swelling, the greater the biodegradability of the hydrogel. The results also indicate that structural factors also influence the degradation of hydrogels.

It is clear from the data in Table 3 that the rate of degradation increases with increasing amount of dextranase.

- 18 • ··· »·· ·· * · · · · · · · · · · · · ·

Table 2

Sample τ (minutes)

THE 18 + 1.5 B 36 + 4.6 C 60 + 4.9 D 255 + 15 E 46 + 1 F 46 + 2 G 33 + 0.6

Table 3

Amount of sample Dextranase (μΐ) r (min)

B 0.5 157 + 5.3 B 3 131 + 14.8 B 12 36 + 4.6

• ·

· *.

- 19 * ··· ···

Example 4

In vivo degradability test of hydrogels The dry weight of six sample plates of mm diameter hydrogel B was determined and pre-swelled in isotonic potassium phosphate buffer (pH 7.4). The plates were implanted into the stomach and caecum of male SD rats weighing 200-300 g each and fixed to the gut wall to prevent gel excretion. The rats are provided with water and food of their choice. At various times (days 1, 2 and 3), the rats were sacrificed and the gels removed. The gels were washed with DMSO and water and dried. The dry weight is determined and the rate of degradation of the gels is given as the percentage degradation (dry weight loss as a percentage of initial dry weight). Initial dry weight ranged from 42 mg to 45 mg.

Figure 4 clearly shows that 3 days after the gels were implanted, the implanted gels decomposed in the appendix, whereas the gels implanted in the stomach did not degrade. This indicates that the gels are degraded in vivo and that this degradation occurs in the caecum and not in the stomach.

Example 5

Incorporation and in vitro release of hydrocortisone in mm diameter and 1.6 mm thickness as in Example 1 · · · · · · · · · · · · · · · · · · · · · · · The hydrogel plates (Sample B) produced were washed with water and dried. After drying, the plates are immersed in hydrocortisone drug solution (72.5 mg / ml) in DMSO. After 24 hours, the gels were dried under vacuum at 50 ° C for 2 days. The release of the hydrocortisone from the plates is studied in 0.1 M acetate buffer, pH 5.4, containing 24 μΐ / ml dextranase or no dextranase. The gel was placed in 5 ml of such release medium and kept in a water bath at 37 ° C. After 8 minutes, 2.5 ml of the enzyme-containing medium and 30 ml of the non-enzymatic medium were taken and replaced with fresh medium.

The amount of liberated hydrocortisone was determined by reversed phase high performance liquid chromatography on a C-18 column using methanol / water (60:40) as the mobile phase with UV detection at 242 nm at an injection volume of 20 μΐ.

After 1 min, 0.72 mg hydrocortisone was released from the gel immersed in the enzyme buffer, while 0.11 mg hydrocortisone was released from the pure gel immersed in the buffer. This indicates that the release is greatly increased in the presence of dextrans.

Figure 5 shows hydrocortisone release profiles from hydrogels. As can be seen from the figure, when dextranase is present in the release medium, the release of hydrocortisone is much faster.

Claims (12)

A drug delivery device comprising a polymer matrix and a drug in or surrounded by the matrix, characterized in that the polymer matrix is a crosslinked hydrogel matrix consisting of a dextranase degradable polymer and a crosslinking bond between the polymer chains. consists of a crosslinking agent. The drug delivery device of claim 1, wherein the dextranase-degradable polymer is dextran. The drug delivery device of claim 2, wherein the dextran is sulfated, alkoxylated, oxidized, or esterified dextran. 4. A drug delivery device according to claims 1 to 4, characterized in that the dextran degradable polymer has a molecular weight of between 10,000 g / mol and 2,000,000 g / mol, preferably between 40,000 g / mol and 2,000,000 g / mol, preferably 70,000 g / mol and 500,000 g / mol. mole. 5. A drug delivery device according to claims 1 to 5, characterized in that the crosslinking agent is a urethane bond forming agent. The drug delivery device of claim 5, wherein the urethane bond-forming agent is hexamethylene diisocyanate or 1,4-phenylene diisocyanate. 7. A drug delivery device according to claims 1 to 3, characterized in that the crosslinking agent is in the hydrogel 0.05 to 25 mol% of monomer units. 8. A drug delivery device according to claims 1 to 3, characterized in that the drug is in homogeneous dispersed form in the hydrogel matrix. 9. A drug delivery device according to any one of claims 1 to 3, characterized in that the matrix surrounds the drug. 10. Procedure 1-9. A pharmaceutical delivery device according to claims 1 to 3, characterized in that: a) dissolving a dextranase degradable polymer in a solvent, b) adding a curing agent capable of crosslinking the polymer by forming covalent bonds, c) allowing the crosslinking agent to react with the dextranase degradable polymer to form a crosslinked hydrogel matrix, and to add the drug to the solution before or after the polymer-crosslinking reaction is complete. 11. The process of claim 10, wherein the drug is surrounded with the polymer and the crosslinking agent before the crosslinking reaction is completed and then the crosslinking reaction is allowed to complete. 12. The process of claim 10, wherein the drug solution or liquid drug is placed in the crosslinked hydrogel such that the drug is pre-dried to absorb the drug.