SK1795A3 - Drug delivery device and method of this production - 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

Controlled release dosage form and process for its manufacture

Technical field

The invention relates to a pharmaceutical form for administration of medicaments to the colon, which comprises a polymer matrix and a drug substance contained in or surrounding the matrix.

BACKGROUND OF THE INVENTION

A large number of drugs are very sensitive to proteolytic enzymes that are contained in gastric juices and the small intestine. Drugs such as peptides and proteins are subject to degradation by proteolytic enzymes, thereby substantially reducing the amount absorbed.

Although oral administration of drugs is much more traditional and patient-friendly, it has hitherto been mostly necessary to administer peptides and proteins of the drug type parenterally.

Studies have 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 suitable technique by which active drug substances are selectively delivered to the colon via the digestive tract.

Polymeric materials such as hydrogels have been widely used in drug delivery systems to delay the release of drugs or in dosage forms sensitive to stimulation. Such hydrogels are described, for example, in Hydrogels in Medicine and Pharmacy, N.A.Peppas (Ed.), CRC.

Press, 1987. The formulations presented in this publication are generally not biodegradable. The release of the pharmacologically active components by which the gel is saturated is usually controlled by simple diffusion in the dosage form. This diffusion is dependent on the water content of the gel. The reference gels 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 crosslinking agent. However, this composition is not useful for oral administration.

U.S. Patent 4,024,073 discloses a hydrogel composition comprising a water-soluble polymer comprising a chelating agent bound to a polymer chain and multivalent metal ions crosslinking polymer molecules through the chelating agent. The hydrogel is useful as a carrier for the time-delayed release of drug 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 US Patent 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 aimed at 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 herein is sensitive to inter-individual variations in intestinal transit and does not release the active ingredient specifically in the colon.

An osmotic pharmaceutical form for the administration of medicaments to the colon is described in patent applications GB 2,166,051 and GB 2,166,052. These dosage forms comprise a layered membrane surrounding the drug-containing space. The membrane achieves a delay in the onset of major drug release. Such osmotic dosage forms have the same disadvantages as the dosage forms described in patent application GB 2 066 070.

The subject of the present invention continues to be related to the publication Chemically Modified Polysaccharides for Enzymatically Controlled Oral Drug Administration (Kost et al., Biomaterials, 11: 695-698, 1990). This article describes an ion-crosslinked 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 therefore drug release is not directed to the colon or colon.

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 pressed matrix of chondroitin. This matrix may disintegrate at any time as it passes through the small intestine. Therefore, this system is not applicable for locally 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 layer are based on polysaccharides such as pectin and / or dextran, forming coacervates by crosslinking with a multivalent cation, being a divalent or trivalent cation.

In the stomach of a patient having normal gastric acid secretion, hydrogen ions penetrate both the cap and the core of the composition, replacing the polyvalent cations by ion exchange, resulting in a significant reduction in the number of complex bonds between the polysaccharide chains, which then more or less hold together effect than 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, a composition of the above type may be capable of delivering the active ingredients to the colon of a patient if the composition has a specific composition for it. Thus, such a composition is commercially unusable.

The use of hydrogels containing biodegradable linkages has been described by Bronsted and Kopecek in Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18, p. 345-346, 1991. These hydrogels are biodegradable due to the content of enzymatically disruptive crosslinks and their swelling is pH-dependent because they contain acidic groups in the polymer backbone. The system utilizes the presence of microbial azoreductases 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 the hydrogel 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 to the colon was also achieved using dextran prodrugs (Larsen et al., Pharm. Res., 6, 995-999, 1989), which release the active substance after cleavage by microbial enzymes that are present only in the colon. The drug is covalently bound to dextran. As the prodrug advances into the colon, bacterial dextranases are capable of cleaving dextran while releasing the drug upon hydrolysis of the covalent bond. The disadvantage of this system lies in the difficulty of administering multiple drugs. Further, the drug substance must contain a modifiable functional group and be sufficiently stable to withstand the reaction conditions necessary for coupling to a dextran carrier.

Thus, it is evident that there is a need for a dosage form for oral administration of drugs with increased colon selectivity.

It is an object of the present invention to provide a dosage form for oral administration of drugs to the colon 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 pharmaceutical dosage form of the invention comprises a polymer matrix and a drug that is contained in or surrounded by the matrix, and characterized in that the polymer matrix is a covalently crosslinked hydrogel matrix containing a dextranase degradable polymer and a crosslinking agent that forms a network. the link between the polymer chains.

As mentioned above, dextranases are present only in the colon. In the dosage form of the invention, the medicament is protected when passing through the stomach and small intestine crosslinked by 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 the release of the drug depends on several factors such as the nature of the dextranase degradable polymer and the crosslinking agent, the degree of crosslinking, the water content of the hydrogel matrix and the final formulation and size of the dosage form. The dosage form of the invention can be made in such a way that virtually all of the drug is released in the colon.

The dextranase degradable polymer for the dosage form 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. Several methods for modifying dextran are known. See, for example, W. M. Meckernan and C. R. Ricketts, Biochem J., 76, p. 117-120, 1960, which teaches the preparation of diethylaminoethyldextran and K. Nagasawa et al., Carbohydr. Res., 21, p. 420-426, 1972, which discloses syntheses of dextran sulfate.

By using modified dextran instead of conventional dextran, 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 also needs to be selected according to which drug the hydrogel matrix is to be saturated so that it does not react with the drug in such a way as to lead to irreversible drug inactivation.

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

The dextranase degradable polymer may have a molecular weight of 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 crosslinking agent may 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 bonds such as hexamethylene diisocyanate and 1,4-phenylene diisocyanate.

The degree of cross-linking and composition of the hydrogel affects the kinetics of degradation, drug saturation, and the overall release characteristics of the hydrogel. This means that a higher degree of crosslinking generally results in slower degradation and release, while a lower degree of crosslinking results in faster degradation and release.

Of course, the effect that the degree of cross-linking has on drug release depends on the size of the drug molecule and the way in which the dosage form saturates the drug. Preferably, the crosslinking agent constitutes 0.05-25 mol% of monomer units in the hydrogel.

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

The dosage form of the invention is also preferred for delayed administration of drugs.

By using the dosage form of the invention, medicaments, e.g. for the treatment of rheumatism and other analgesics, the patient in the evening before sleep, and these medicines will work in the morning, since the time required to transfer the dosage form to the colon is about 8 hours.

The hydrogel matrix may 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. the drug is surrounded by a thicker layer of hydrogel matrix.

Methods for introducing drugs into a hydrogel are well within the skill of those skilled in 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 medicament is homogeneously dispersed in a crosslinked hydrogel matrix.

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

The dosage form of the invention may contain more than one drug, e.g. it may comprise one high molecular weight drug in the hydrogel matrix cavity and another low molecular weight drug evenly distributed throughout the matrix.

It will be apparent to those skilled in the art that other combinations are also possible with drugs that are released in the stomach or small intestine.

The method of the invention comprises the following steps:

a) dissolution of the dextranase degradable polymer in the 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 dosage form may be fed with the drug before the cross-linking reaction is completed using several methods. These methods are well known to those skilled in the art and are described, for example, in S. Z. Song et al., J. Pharm. Sci., 70, 216-219,1981.

In a preferred embodiment, the medicament is formulated after completion of the cross-linking 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 a liquid drug or drug solution and allowing it to swell.

c) if desired, the hydrogel is dried.

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 dissolution of the dextran to a clear, slightly viscous solution, 86 μΐ (0.46 mmol, i.e. about 5 mol%) of hexamethylene diisocyanate (abbreviation HDI, crosslinking agent) was added. This was done in a thoroughly dried glass flask, since even small amounts of water interfere with the crosslinking reaction. Then, the solution was transferred to the foil reaction mold by means of a 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 spacing between the blocks can be controlled by means of spacers to obtain a foil of the desired thickness. The temperature was set at 70 C. At this temperature, the crosslinking reaction lasted 24 hours.

In a similar manner, four additional 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.

The molecular weight of dextran was also changed. Dextran hydrogels of 10, 500 and 2000 (molecular weights of 10,000, 500,000 and 2,000,000) were produced.

Table 1 shows a schematic overview of the synthesized gels.

Table 1

sample Dextran (molecular weight) DMSO (% vol) HDI (mol%) A 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

The volume percentages were calculated in relation to the volume of the resulting reaction mixture. The molar percentages were calculated based on 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 Example 1 of Sample A-G was examined using three disks punched from each hydrogel. The mass of 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 the dry gel.

Figure 1 shows the dependence of the equilibrium degree of swelling of hydrogels on the concentration of DMSO in the reaction mixture in 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.

Fig. 2 shows that the equilibrium degree of swelling decreases with increasing crosslinking density.

FIG. 3, it can be seen 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). The 5 mm diameter, 1.6 mm thick hydrogel film discs, prepared as described in Example 1, were chopped and swollen equilibrated 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 μext dextranase. The disc mixture was then tempered in a 37 ° C water bath and the time (t) required to completely dissolve the discs was recorded. Gel degradation was monitored by thickness reduction.

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

Table 3 shows that the degradation rate increases with increasing amount of dextranase.

Table 2

Sample t (min)

A 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 dextranase

(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 preloaded in isotonic potassium phosphate buffer pH 7.4. Each disc was placed in a gauze bag. These pockets were implanted in the stomach and caecum of male SD rats (200-300 g) and secured against intestinal excretion. The rats were then provided with feed and water at will. After various times (1, 2 and 3 days) the rats were then sacrificed, the gels were removed, washed in DMSO and water and dried. Dry weight was recorded and the degradation of the gels was evaluated in% degradation (dry weight loss from the original dry weight). The initial dry weight was between 42 and 45 mg.

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

Example 5

Hydrocortisone saturation and release in vitro

The hydrogel discs prepared by the procedure of Example 1, 5 mm in diameter and 1.6 mm thick (sample B), were 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 µΐ injection volume.

After 30 minutes, 0.72 mg of hydrocortisone was released from the gel by immersion in enzyme-containing buffer compared to 0.11 mg of the gel immersed in pure buffer. This indicates that release is very markedly increased in the presence of dextranases.

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

Claims (12)

PATENT CLAIMS A controlled release dosage form comprising a polymeric matrix and a drug contained therein or encapsulated therein, wherein the polymeric matrix is a crosslinked hydrogel matrix comprising a dextranase degradable polymer and a crosslinking agent that forms covalently bonded crosslinks between the polymer chains. The dosage form of claim 1, wherein the dextranase degradable polymer is dextran. Pharmaceutical form according to claim 2, characterized in that the dextran is sulphated, alkoxylated, oxidized or esterified. The dosage form according to claims 1 to 3, characterized in that the dextran degradable polymer has a molecular weight of between 10 000 to 2 000 000 g / mol, preferably between 40 000 to 2 000 000 g / mol and in particular between 70 000 to 2 000 000 g / mol. 500,000 g / mol. Pharmaceutical form according to claims 1 to 4, characterized in that the crosslinking agent is an agent which forms urethane bonds. The dosage form of claim 5, wherein the urethane bonding agent is hexamethylene diisocyanate or 1,4-phenylene diisocyanate. Pharmaceutical form according to claims 1 to 6, characterized in that the crosslinking agent constitutes 0.05 to 25 mol% of monomer units in the hydrogel. Dosage form according to claims 1 to 7, characterized in that the medicament is uniformly dispersed in the hydrogel matrix. Dosage form according to claims 1 to 7, characterized in that the medicament is surrounded by a hydrogel matrix. A process for the manufacture of a dosage form according to claims 1 to 9, characterized in that it is present a) dissolves dextranase degradable polymer in solvent, b) adding to the solution a crosslinking agent capable of crosslinking the polymer by covalent bonds; c) reacting the crosslinking agent with a dextranase degradable polymer until a crosslinked hydrogel matrix is obtained, said solution being saturated with the drug before or after the reaction between the polymer and the crosslinking agent. The method of claim 10, wherein the drug is surrounded by a polymer and a cross-linking agent before the cross-linking reaction is completed, whereupon the cross-linking reaction is allowed to terminate. The method of claim 10, wherein the cross-linked hydrogel is saturated with the drug in solution or in liquid form by absorption into the pre-dried hydrogel. Pv f ¥ - 9r 1/5 Equilibrium degree of swelling (Weight of the swollen gel in ratio Oh j. % DMSO in the reaction mixture / V? 2/5 Fig. 2 Steady-state swelling (Weight of swollen gel relative to dry gel weight) 3/5 Steady-state swelling (Weight of swollen gel relative to dry gel weight) 70000 500000 2000000 Molecular weight of dextran Pi / n ~ qr M 1 + - <tr 4/5% degradation Time (days) r * 'f ¥ -? R 5/5 Amount of hydrocortisone released (mg)