CZ3895A3 - Apparatus for administration of therapeutical compounds and process for producing thereof - 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

A drug delivery device and method thereof.

5. X - uO ° σι

FIELD OF THE INVENTION The invention relates to an apparatus for administering chemical substances to the colon. The device comprises a polymer matrix and a drug substance contained therein or surrounding it.

A large number of active substances are sensitive to proteolytic enzymes which are contained in gastric juices and small intestine. Active substances, such as peptides and proteins, are subject to degradation by proteolytic enzymes, thereby substantially reducing the amount absorbed.

Although oral administration of the drug is much more traditional and patient-friendly, most peptides and proteins of the type still need to be administered parentally.

Research has shown that the concentration of proteolytic enzymes in colon juices is much lower than that in gastric and small intestine juices.

It would be highly advantageous to find a viable technique by which active drug substances are selectively delivered to the colon by the digestive tube.

Polymeric materials such as hydrogels have already been extensively used in carrier systems to delay the release of active ingredients or as stimulation sensitive devices. Such devices are described, for example, in Hydrogels in Medicine and Pharmacy, N.A.Peppas (Ed.), CRC Press, 1987. The formulations disclosed in this publication are generally not biodegradable. The release of the pharmacologically active components through which the gel is saturated is usually controlled by simple diffusion in the device. This diffusion is dependent on the water content of the gel. The gels cited herein are therefore not useful for delivering drugs to specific areas of the intestines after oral administration.

Patent application EP 357 401 discloses a biodegradable hydrogel matrix comprising a protein, a polysaccharide and a cross-linking agent. However, this composition is not useful for oral administration.

U.S. Pat. No. 4,024 0.73 discloses a hydrogel composition comprising a water-soluble polymer comprising a chelating agent attached to the polymer chain and polyvalent metal ions transversely connecting the polymer molecules through the chelating agent. Hydrogel is useful as a carrier for the time-delayed release of active substances and preparations not directed to the colon.

Japanese patents JP 1 156 912, JP 62 010 012 and JP 5 721 315, DE 3,400,106 and U.S. Pat. No. 4,496,553 disclose the preparation of compressed slow release tablets using soluble polymers or polysaccharides. These are always conventional tablets, disintegrating in a time-dependent manner and not specifically targeted to the colon. '. :. . GB 2 066 070 describes a pharmaceutical composition in the form of a tablet for the release of the active ingredient in the colon. This tablet contains in the middle an active component coated with a coating of cellulose and its derivatives. The coating is biodegradable by bacteria present in the colon. The disadvantage of this system, however, is that the coating may dissolve in the stomach or upper digestive tract. Therefore, the system described is sensitive to inter-individual variations in transit. and does not release the active ingredient specifically in the colon.

to

Osmotic colon drug delivery devices are described in GB 2,166,051 and GB 2,166,052. These devices include a laminate membrane surrounding the drug containing space. A delay in the onset of major drug release is achieved by the membrane. Such osmotic drug delivery devices have the same disadvantages as those described in patent application GB 2 066 070.

Areas.. . invention. further ... concerns. Chemically-modified polysaccharides for enzymatically-controlled oral drug delivery (Kost et al., Biomaterials, 11, 695-698, 1990). This article describes an ion-cross-linked starch system that is used for the controlled release of macromolecules into the. intestines. The system advantageously utilizes the presence of amylases in the small intestine and is therefore not directed to colon or colon.

i ^r

Recently, Rubinstein et al. (Pharm. Res., 9, 276-278, 1992) administration of the drug to the colon using a chondroitin matrix. The system consists of a drug embedded in a compressed matrix of chondroitin. This matrix may disintegrate at any time as it passes through the small intestine. Therefore, this system is not applicable to site-specific drug delivery to the colon.

WO 92/00732 discloses a composition for oral administration of a therapeutically active agent to the colon. The composition comprises a core of a matrix in which at least one active agent is stored or dispersed and an outer cover layer without any active ingredient. Both the matrix core and the outer cover are chemically based on polysaccharides such as pectin, and / or dextran, forming coacervates by crosslinking with a polyvalent cation, which is a divalent or trivalent cation

In the stomach of a patient who has normal gastric acid secretion, hydrogen ions penetrate both the cap and the nucleus, replacing polyvalent cations by ion exchange, resulting in a significant reduction in the number of complex bonds between the polysaccharide chains, which more or less hold together more sterically than by linking to cations.

That is, the composition disintegrates more or less as it passes through the stomach and small intestine, and that this disintegration is largely dependent on the presence of other cations, the residence time of the composition, and in particular how gastric acid secretion works in the particular patient being treated. In other words, the composition may be able to deliver the active ingredients to the colon of the patient if the composition has a specific composition for it.

Therefore, such a composition is commercially unusable.

The use of hydrogels containing biodegradable bonds has been described by Bronsted and Kopeček in Proceed. Intern. Symp. Control. Rel. Bioáct. Mater., 18, pp. 345-346, 1991. These hydrogels are biodegradable due to the content of enzymatically disruptive crosslinks and their swelling is pH-dependent because they contain acid groups in the polymer backbone. The system utilizes the presence of microbial azoreductase in the colon. Hydrogels disintegrate after degradation of the crosslinks and release of the polymer backbone.

By using these acid hydrogels, degradation and release of the drug in the stomach can be substantially prevented. However, the degradation of hydrogels and the subsequent release of the drug into the colon is very slow and thus only part of the total amount of drug can be released when passing through the colon.

Administration of the drug into the colon was also achieved using dextran drug precursors (Larsen et al., Pharm. Res., 6, 995-999, 1989), which release the active substance upon cleavage by microbial enzymes that are only present in the colon. The drug is covalently bound to dextran. As the prodrug advances into the colon, bacterial dextranases are able to cleave dextran while releasing the drug upon hydrolysis of the covalent bond. The disadvantage of this system is the difficulty of administering multiple drugs. Further, the drug substance must contain a modifiable functional group and be stable enough to withstand the reaction conditions necessary for attachment to the dextran carrier.

It is therefore evident that there is a need for an oral drug delivery device with increased colon selectivity.

It is an object of the present invention to provide an oral drug delivery device that can deliver one or more drugs to the colon without substantially losing the drug in the stomach, small intestine and stool.

SUMMARY OF THE INVENTION

The drug delivery device of the present invention comprises a polymer matrix and a drug contained within or surrounded by the matrix and wherein the polymer matrix is a covalently crosslinked hydrogel matrix containing a dextranase degradable polymer and a crosslinker that forms cross-links between polymer chains.

As mentioned above, dextranases are present only in the colon. In the drug delivery device of the invention, the drug is protected by passing through the stomach and small intestine cross-linked with a dextranase degradable polymer. As the polymer matrix advances into the colon, it is decomposed by the dextranase and the drug is released.

The rate of degradation of the polymer matrix, and hence drug release, depends on several factors such as the nature of the dextranase degradable polymer and crosslinker, the degree of crosslinking, the water content of the hydrogel matrix, and the final configuration and size of the device. The device according to the invention can be manufactured in such a way that virtually all the drug is released in the colon.

The dextranase degradable polymer for the device of the invention must be substantially resistant to the digestive juices of the stomach and small intestine.

Preferably, the dextranase degradable polymer is > dextran or modified dextran. It is known to modify dextran in several ways. See, for example, W.M.Meckernan and C.R. Ricketts, Biochem J.. 76, pp. 117-120, 1960, which discloses the preparation of diethylaminoethyldextran and K. Nagasawa et al., Carbohydr. Res., 21, pp. 420-426, 1972, which discloses syntheses of dextran sulfate.

Using modified dextran instead of conventional dextran

Ό a more hydrophobic or hydrophilic hydrogel matrix can be obtained, depending on its chemical nature. This can be used to control the swelling properties of the hydrogel matrix. The dextranase degradable polymer should also be selected according to the drug to which the hydrogel matrix is to be saturated, so that it does not react with the drug in a manner that would lead to irreversible drug inactivation.

Sulphated, alkoxylated, oxidized or esterified dextran is particularly preferred.

The dextranase degradable polymer may have a molecular weight between 10,000 and 2,000,000 g / mol, preferably between 40,000 and 2,000,000 g / mol.

When the dextranase degradable polymer is dextran, the optimal molecular weight is between 70,000 and 500,000.

The cross-linking agent can be any non-toxic agent that is capable of forming cross-links of the polymeric structure. The polymer may be held together by covalent bonds such as a urethane, ester, ether, amide, carbonate or carbamate bond. A preferred crosslinking agent is a diisocyanate that forms urethane linkages such as hexamethylene diisocyanate and 1,4-phenylene diisocyanate.

«. and

The degree of crosslinking and composition of the hydrogel affects the kinetics of degradation, saturation by the drug, and the overall characteristics of its release from the matrix. That is, a higher degree of crosslinking generally results in slower degradation and release, while a lower degree of crosslinking results in faster degradation and release. _r

Of course, the effect that the degree of crosslinking has on drug release is dependent on the size of the drug molecule and the way the device is saturated with the drug. Preferably, the crosslinking agent forms 0.05 in the hydrogel. up to 25 mol% of monomer units.

! The medicament may be in principle of any type. The device according to the invention is particularly advantageous for use in the administration of medicaments for the treatment of colon diseases, e.g. steroids, 5-aminosalicylic acid, anti-inflammatory drugs, anticancer drugs, enzymatic drugs and bacterial cultures, or for administration of drugs in the stomach and / or small intestine unstable, for example peptides such as insulin, vasopressin, or growth hormones, proteins, enzymes and vaccines.

I. ~ '

The device according to the invention is also advantageous for time-delayed drug delivery.

By using the device according to the invention, medicaments, e.g. for the treatment of rheumatism and other analgesics, can be administered to a patient in the evening before falling asleep, and these medicines will be effective in the morning, since * '1

The hydrogel matrix can be saturated with the drug in several ways. For example, the medicament, or a gelatin capsule containing it, may be coated with a hydrogel matrix, or the medicament may be contained within a cavity of the hydrogel body, i.e., the medicament is surrounded by a thicker layer of hydrogel matrix.

Methods for introducing drugs into a hydrogel are well within the skill of the art and are described, for example, in S. W. Kim et al., Pharm. Res., 9, 283-290, 1992.

In a preferred embodiment of the invention, the drug is homogeneously dispersed in a cross-linked hydrogel matrix.

Depending on how the drug is introduced, the hydrogel matrices may be formed as capsules, tablets, films, microspheres, and the like. The composition formed from polymeric matrices may comprise known pharmaceutical carriers or excipients, adjuvants, etc.

The device according to the invention may comprise more than one

For example, the drug may comprise one high molecular weight drug in the hydrogel matrix cavity and another low molecular weight drug uniformly dispersed throughout the matrix.

One skilled in the art would appreciate that other combinations are possible with drugs that are released in the stomach or small intestine.

The method of the invention comprises the following steps:

a) dissolving the dextranase degradable polymer in a solvent,

b) adding a crosslinking agent capable of crosslinking the polymer by covalent bonds to the solution;

c) allowing the crosslinking agent to react with the dextranase degradable polymer until a crosslinked hydrogel matrix is obtained.

The device can be saturated with drug before the cross-linking reaction is completed using several methods. These methods are generally known to those skilled in the art and are described, for example, in the publication

S.Z.Song et al., J. Pharm. Sci., 70, 216-219 (1981).

In a preferred embodiment, the medicament is introduced into the device after completion of the crosslinking reaction in a manner that utilizes the following steps:

a) the hydrogel matrix is pre-dried, preferably to a water content below 30% by weight, preferably below 10% by weight; %.

b) contacting the dried hydrogel matrix with the liquid drug or drug solution and swelling.

c) If desired, the hydrogel is dried.

This latter method represents a very simple production of the device according to the invention by which the medicament is evenly dispersed.

A set of examples is given below to describe the invention.

*

Drawing overview *

Giant. 1 is a graph depicting the equilibrium degree of swelling of the device of the invention on the DMSO (dimethylsulfoxide) concentration.

Giant. 2 is a graph depicting the equilibrium degree of swelling of the device of the invention on the concentration of crosslinker used.

Fig. 3 is a graph showing the equilibrium degree of swelling of the device of the invention on the molecular weight of dextran.

Giant. 4 is a graph showing the degradation of the device of the invention in appendicitis and stomach over time.

Giant. 5 shows the release characteristics of hydrocortisone from the device according to the invention

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of biodegradable dextran hydrogels

1.5 grams (9.25 mmol of glucose units) of dextran 70 (molecular weight 70,000, commercially available from Pharmacia) was dissolved in 8.5 ml (85% by volume) of anhydrous dimethylsulfoxide (DMSO). Immediately after dissolving dextran to a clear, slightly viscous solution, 86 μΐ (0.46 mmol) was added.

i.e. about 5 mol. %) hexamethylene diisocyanate (abbreviation HDI, crosslinking agent). This was done in a thoroughly dried glass flask as a small amount of water disturbs the crosslinking reaction. The solution was then transferred to the reaction form by syringe with a needle. The mold consisted of two aluminum blocks with a water jacket, coated with Teflon, between which a solution was placed.

The distance between the blocks can be adjusted by means of spacers to obtain a foil of the desired thickness. The temperature was set to 70 ° C. At this temperature, the crosslinking reaction persisted. .. ..... i '24 hours'.

In a similar manner, hydrogels containing dextran 70 and varying amounts of HDI and DMSO were synthesized. Two gels had 2.5 and 10 mol% HDI and two had 80 and 90 vol% DMSO. 3 ií

AND

The molecular weight of dextran was also varied. Were>;

produced hydrogels from dextran 10, 500 and 2000 (molecular weight) of 10,000, 500,000 and 2,000,000).

. . . '· I ·:

Table 1 shows a schematic overview of the synthesized gels. '

Table 1

Example Dextran (molecular mass) * DMSO (v / v) HDI (mol%) AND 70 000 85 2.5 (B) 70 000 85 5 C 70 000 85 ¹⁰ D 70 000 ⁸⁰ 10 E 70 000 rt 90 10 F 500 000 85 5 G 2 000 000 85 5

The percentages by volume were calculated based on the basis of the resulting volume of the mixture. The molar percentages of dextran were calculated as the molar glucose content of the amount of dextran used.

Example 2

Determination of the equilibrium degree of swelling of biodegradable dextran hydrogels

The equilibrium degree of swelling of the hydrogels prepared according to Examples 1 / A-G was examined using three disks punched from each hydrogel. The mass of the hydrogels swollen in water and DMSO was determined. The gels were washed with water and then dried at room temperature for 2 days and under vacuum at 40-50 ° C for 2 days. The equilibrium degree of swelling was evaluated as the ratio of the weight of the swollen to dry gel.

Fig. 1 shows the dependence of the equilibrium degree of swelling of hydrogels on the concentration of DMSO in the reaction mixture during their preparation. It can be seen that increasing the amount of DMSO in the reaction mixture results in an increase in the equilibrium degree of swelling of the obtained hydrogel. This phenomenon is more evident in DMSO than in the case of water. Figure 2 shows that the equilibrium degree of swelling decreases with increasing crosslink density.

It can be seen from Fig. 3 that the change in molecular weight of dextran has no significant effect on the equilibrium degree of swelling.

*

The equilibrium degree of swelling is greater in DMSO than in water. Therefore, DMSO appears to be a good example of a suitable drug saturation environment.

Example 3

Determination of degradation of hydrogels in vitro

The degradation of hydrogels in vitro was tested using dextranase (50 kilo Dextranase Units / g). 5 mm diameter and 1.6 mm thick hydrogel film discs prepared as described in Example 1 were chopped and swelled to equilibrium in 0.1 M acetate buffer at pH

5.4. After equilibrium swelling was achieved, the discs were transferred to an enzyme mixture consisting of 1 ml of 0.1 M acetate buffer pH 5.4 and 0.5, 3 or 12 μΐ dextranases. The mixture with the discs was then tempered in a 37 ° C water bath and the time (t) required to completely dissolve the discs was recorded. The degradation of the gels was monitored by thickness reduction.

Table 2 shows the time t for different gels where the enzyme mixture contains 12 μΐ dextranases / ml buffer. As the crosslinking density increases, so does t, and therefore degradability decreases. This also applies to the equilibrium swelling, whose higher value means higher degradability of the hydrogel. The results also show the influence of structure / · on degradability of hydrogels.

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

Table 2

Sample -1 (min) AND 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

Sample Amount of dextranase (μΐ) t (min) (B) 0.5 . 157 ± 5.3 (B) 3 131 ± 14.8 (B) 12 36 ± 4.6

Example 4

Determination of hydrogel degradability in vivo

The dry weight of six 5 mm diameter discs was recorded and the discs were pre-swollen in isotonic potassium phosphate buffer pH 7.4. Each disc was placed in a gauze bag. These bags were implanted in the stomachs and caecum of male SD rats (200-300 g) and secured against excretion via the intestinal route. The rats were then fed ad libitum and water. After various times (1, 2 and 3 days), the rats were sacrificed, the gels were removed, washed in DMSO and water, and dried. Dry weight was recorded and degradation of the gels was evaluated in% degradation (dry weight loss from original dry weight). The initial dry weight was between 42 and 45 mg.

Giant. 4 shows that after 3 days gels implanted in appendix were degraded while gels implanted in the stomach were not degraded.

Example 5

Hydrocortisone saturation and its release in vitro

The hydrogel discs prepared by the procedure of Example 1 with a diameter of 5 mm and a thickness of 1.6 mm (sample Β) were

- 14 washed with water and dried. After drying, they were immersed in a solution of the hydrocortisone drug in DMSO (72.5 mg / ml). After 24 hours, the gels were dried under vacuum at 50 ° C for 2 days. The release of hydrocortisone from the disks was tested in 0.1 M acetate buffer, pH 5.4, both in the presence of 24 μΐ dextranase / ml buffer and in the absence of dextranase. The gel was immersed in 5 ml of the release rate medium and left in a 37 ° C water bath. At 8 minute intervals, if enzyme was present and 30 minute intervals, if absent, 2.5 ml samples were taken and the missing volume was replaced with fresh solution. The amount of hydrocortisone released was determined by reverse phase HPLC on a C-18 column using a 60:40 methanol / water mixture as the mobile phase and UV detection at 242 nm and a 20 g injection volume.

After 30 minutes, 0.72 mg of hydrocortisone was released from the gel by elution with the enzyme-containing buffer and, in comparison, 0.11 mg of gel was eluted from the gel in pure buffer. This shows that the release * is greatly increased in the presence of dextranases.

»'<·

Giant. 5 shows the release characteristics of hydrocortisone from hydrogels. When dextranase is present in the environment, a much faster release of hydrocortisone is achieved.

Claims (11)

PATENT CLAIMS A drug delivery device comprising or surrounded by a polymeric matrix, wherein the polymeric matrix is a crosslinked hydrogel matrix comprising a polymer degradable by dextranase and a crosslinking agent that forms covalently bonded crosslinks between the polymer chains. . Medicament delivery device according to claim 1, characterized in that the dextranase degradable polymer is dextran. Medicament delivery device according to claim 2, characterized in that the dextran is sulphated, alkoxylated, oxidized or esterified. Medicament delivery device according to claims 1 to 3, characterized in that the dextran degradable polymer has a molecular weight between 10 000 and 2 000 000 g / mol, preferably between 40 000 and 2 000 000 g / mol and in particular between 70 000 and 2 000 000 g / mol. 000 and 500,000 g / mol. Medicament delivery device according to claims 1 to 4, characterized in that the enhancer is an agent that forms urethane bonds. Medicament delivery device according to claim 5, characterized in that the urethane bonding agent is hexamethylene diisocyanate or 1,4-phenylenediisocyanate. Medicament delivery device according to claims 1 to 6, characterized in that the crosslinking agent comprises 0.05 to 25 mol% of monomer units in the hydrogel. AVF.VrXTBí mnnasuru »; 1Ï AND Medicament delivery device according to claims 1 to 7, characterized in that the medicament is uniformly dispersed in the hydrogel matrix. A drug delivery device according to claims 1 to 7, characterized by no hydrogel matrix. e team in , ze the drug is encircled- 10. Method of production equipment according to claims 1 to 9, characterized by e team ^- -that- se při him ^_ a) dissolves dextranase degradable polymer in solvent, b) adding to the solution a crosslinking agent capable of crosslinking the polymer by covalent bonds; c) allowing the crosslinker to react with the polymer; degradable dextranase until a cross-linked hydrogel matrix is obtained, wherein said solution is saturated ..... drug before completion of the reaction between the polymer and the crosslinking agent, or. after completion of this reaction. and 11. The method of claim 10, wherein the drug is surrounded by a polymer and a crosslinking agent prior to completion of the crosslinking reaction, whereupon the crosslinking reaction is allowed to terminate. . <. ii .. ... .X The method of claim 10, wherein the cross-linked hydrogel is saturated with the drug in solution or in liquid form by absorption into a pre-dried hydrogel.