RU2139093C1 - Medicinal agent delivery device and method of its manufacture - Google Patents

Abstract

FIELD: pharmaceutics. SUBSTANCE: device for peroral delivery of medicinal agent acting in large intestine has hydrogel base. Medicinal agent is in this base or is surrounded with it. Base is obtained by interaction of dextran or its derivatives with agent of cross-bond formation. Agent provides for system with covalent bonding between polymer chains formed by cross- bonds. For example, agent may form urethan bonds. Device is obtained by dissolving of the above-indicated polymer with addition of cross-bond formation agent into solution. Medicinal agent is introduced before or after their interaction. Medicinal agent may be introduced in form of solution or liquid into gel obtained as a result of interaction of polymer with agent. EFFECT: device makes it possible to avoid loss of medicinal agent in stomach, small intestine and with feces. 9 cl, 5 ex, 3 tbl, 5 dwg

Description

 The present invention relates to drug delivery devices for administering drugs to the large intestine and including a polymer base and a drug contained in or surrounded by a base.

 A large number of drugs has a high sensitivity to proteolytic enzymes contained in the digestive juices of the stomach and small intestine. Medicines, such as peptides and proteins, are degraded by proteolytic enzymes, thereby substantially reducing absorption.

 Despite the fact that the most common and acceptable for the patient is the appointment for oral administration (oral administration), the most common way of delivering drugs, such as peptides and proteins, is parenteral administration.

 Studies have shown that the concentration of proteolytic enzymes in the juices of the colon is much lower than the concentration in the juices of the stomach and small intestine.

 Therefore, it was very useful to find a suitable method for delivering drugs of choice to the large intestine by administration through the digestive tract.

 Polymeric materials such as hydrogels are widely used in drug transfer systems for controlled release or used as stimulating sensors. Such devices, for example, are described in the work of N.A. Peppasa (ed.) Hydrogels in Medicine and Pharmacy), CRC Press, 1987. The techniques for preparing drugs described herein are generally not biodegradable. Isolation of pharmacologically active agents “loaded” into such gels is usually controlled by simple diffusion in a device that depends on the water content in the gel. Therefore, these gels are not suitable for delivering drugs to specific areas of the intestine after oral administration.

 EP patent application No. 357401 discloses a biodegradable hydrogel base comprising a protein, a polysaccharide and a crosslinking agent. However, this composition is not suitable for oral administration.

 US Pat. No. 4,024,073 discloses a hydrogel mixture comprising a water-soluble polymer containing a chelating agent bonded to a polymer chain and a polyvalent metal ion forming cross-links of polymer molecules via a chelating agent. Hydrogel is useful as a carrier for the synchronized release of drugs and drugs and is not intended for the large intestine.

 Japanese patents JP 1156912, JP 62010012, JP 5721315, Germany DE 3400106 and US N 4496553 describe the preparation of compressed tablets for the slow release of drugs using soluble polymers or polysaccharides. All of them are ordinary tablets, split according to time, and are not intended specifically for the large intestine.

 British Patent Application GB 2066070 describes a tablet preparation technology for the release of an active substance in the colon. This tablet contains the active ingredient in the center, coated with a shell consisting of cellulose and its derivatives.

 The membrane can be destroyed by bacteria present in the large intestine. However, the disadvantage of this system is that the membrane can dissolve in the stomach or in the upper gastrointestinal tract. Therefore, the patent describes a system that is sensitive to time passing through the intestines in various people and which does not release active substances specifically in the large intestine.

 Osmotic drug devices for delivering a drug to the large intestine are described in UK patent applications Nos. 2166051 and 2166052. These devices comprise a laminate surrounding the drug-containing space. The shell leads to a delay in the onset of significant release of the drug. Such osmotic drug devices have the same disadvantages as the devices disclosed in UK patent application N2066070.

 A publication related to the field of the present invention is the work of: Chemically modified polysaccharides for enzyme-controlled oral drug delivery. (Kost et al., Journal of Biomaterials, N 11, p. 695-698, 1990). This work describes a starch system with ionically formed cross-links used for controlled excretion of macromolecules in the intestine. The system takes advantage of the presence of amylases in the small intestine and is therefore not intended to be excreted in the large intestine or colon.

 Recently, Rubinstein et al. (Journal of Pharmacological Research, N9, pp. 276-278, 1992) described the delivery of drugs to the large intestine using a chondroitin base. The system consists of a drug embedded in a compressed chondroitin base. This base can be broken down at any time during passage through the small intestine. Thus, this system is not suitable for delivering special-purpose drugs to the large intestine.

 WO 92/00732 describes a composition for oral administration of a therapeutic agent to the large intestine. The composition contains a core core having an active substance or substances dispersed therein, and an outer coating layer without any active substance. Both the main core and the outer covering layer are based on polysaccharides such as pectin and (or) dextran, forming a coacervate by crosslinking with a polyvalent cation, the cation being divalent or trivalent.

 In the patient’s stomach, which has the normal function of gastric acid, hydrogen ions penetrate the outer layer and core of the composition and, by ion exchange of hydrogen ions with multivalent cations, leave polysaccharide chains that are not highly bonded and more or less keep the composition united by means of spatial effects rather than cationic compounds.

 This means that the composition more or less disintegrates during passage through the stomach and small intestine and this decay during this passage strongly depends on the presence of other cations, the residence time of the composition and, in particular, on the activity of the stomach acid of each patient. In other words, the composition of the type described above may be able to deliver the active substance to the patient’s colon, if the composition is prepared specifically for this patient. Therefore, such a composition is not suitable from a commercial point of view.

 The use of hydrogels containing biodegradable bonds has been previously described by Bronstead and Kopecek in Proceedings of the International Symposium on the Management of Bound Bioactive Materials, N 18, pp. 345-346, 1991. Hydrogels exhibit a hydrogen-dependent swelling due to embedded acid groups in the polymer base chains, and biodegradability due to enzymatically unstable crosslinks. The system uses the presence of microbial azo reductases in the large intestine. Hydrogels decompose after the destruction of cross-links and the release of the polymer main chain.

 Using these acid hydrogels, some significant degradation and release of the drug in the stomach can be avoided. However, the destruction of the hydrogel and, thus, the release of the drug in the colon occur very slowly, and with the passage of the colon, only part of the drug can be released.

 The supply of drugs to the large intestine was obtained using dextran prodrugs (Larsen et al., Pharmacological Research journal, N 6, pp. 995-999, 1989), which release the active substance after cleavage by microbiological enzymes present only in large intestine. The drug was covalently linked to dextran.

 When the prodrug reached the large intestine, bacterial dextranases were able to destroy the dextran secreting the drug after hydrolysis of the covalent bond. The disadvantage of this system is the serious problem of drug loading. In addition, the drug must have a suitable functional group for modification and be able to withstand the experimental conditions for communication with a dextran carrier.

 Therefore, it is obvious that there is a need for an oral drug delivery device with improved selectivity to the large intestine.

 An object of the present invention is to provide such an oral drug delivery device for administering a drug to the large intestine, by using which one or more drugs can be delivered to the large intestine without significant loss of the drug in the stomach, small intestine and feces.

 A drug delivery device according to the invention includes a polymer base and a drug contained in or surrounded by a base, and characterized in that the polymer base is a covalent crosslinked hydrogel base including a degradable dextranase polymer and a crosslinking agent providing branched bond between polymer chains.

 As mentioned above, dextranases are present only in the large intestine. In the drug delivery device of the invention, the drug is protected by a crosslinked degradable dextranase polymer as the device passes through the stomach and small intestine. When it reaches the large intestine, the polymer base is destroyed by dextranase and a drug is released.

 The rate of destruction of the polymer base and, therefore, the release of the drug depends on several factors, such as the choice of the polymer decomposable by dextranase, the crosslinking agent, the degree of crosslinking, the water content of the hydrogel base and the configuration and size of the resulting device. The device according to the invention can be designed so that almost all of the drug is excreted in the large intestine.

 Destructible dextranase polymer in the device according to the invention should be essentially resistant to the digestive juices of the stomach and large intestine.

 Dextranase degradable polymer is preferably dextran or a modified dextran. Several methods for modifying dextran are known. See, for example, the work of U.M. Makernana and S.R. Ricketts's Biochemical Journal, N 76, pp. 117-120, 1960, concerning the preparation of diethylaminoethyldextran. and the work of K. Neigasawa et al. in the Journal of Carbohydrate Research, N 21, pp. 420-426, 1972, concerning the synthesis of dextran sulfate.

 Using modified dextran instead of ordinary dextran, a hydrogel base with a more hydrophobic or more hydrophilic as well as a charged character can be obtained. This can be used to control the swelling properties of the hydrogel base. A hydrogel degradable by dextranase is also selected depending on which drug is to be loaded into the hydrogel base so that the dextranase degradable polymer does not react with the drug in a manner that inactivates the drug.

 Particularly preferred is sulfated, alkoxylated, oxidized or etherized dextran.

 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.

 If the polymer degradable by dextranase is dextran, the optimum molecular weight is between 70,000 and 500,000.

 The crosslinking agent can be any non-toxic agent that is capable of providing a branched bond of the polymer structure. The polymer can be held together by covalent bonds, such as urethane, ester, ether, amide, carbonate or carbonate compounds. As a crosslinking agent, a diisocyanate which provides urethane bonds such as hexamethylenediisocyanate and 1,4-phenylenediisocyanate is preferred.

 The degree of crosslinking in a hydrogel, similar to the composition of the hydrogel itself, affects the kinetics of decomposition, filling, and the general profile of base release. That is, a higher degree of crosslinking usually leads to a slower decomposition and release, while a lower degree of crosslinking will lead to a faster decomposition and excretion.

 Of course, the effect that the degree of crosslinking has on the release of the drug depends on the size of the molecules of the drug and how the drug fills the base. The crosslinking agent is preferably 0.05-25 molecular percent of the monomer units in the hydrogel.

 In principle, the drug can be any type of drug. The device of the invention is particularly advantageous when drugs are prescribed for the treatment of diseases in the colon, for example, steroids, 5-aminosalicylic acid, anti-inflammatory drugs, anti-cancer agents, an enzyme substance and bacterial cultures, or for the administration of drugs that are unstable in the stomach and (or) the small intestine, for example, peptides such as insulin, a vasodilator or growth hormones, proteins, enzymes and vaccines.

 The device according to the invention is also advantageous for use in the administration of drugs with delayed action.

 By using the device of the invention according to the invention, drugs such as substances for treating rheumatism or other analgesic substances can be administered to the patient while he goes to bed, and they will be effective in the morning if the time of penetration of the device into the large intestine is about 8 hours.

 The drug can be loaded into the hydrogel base in several ways. For example, the drug or gelatin capsule containing the drug can be coated with a hydrogel base, or the drug can be contained in the cavity of the hydrogel device, that is, the drug is surrounded by a thicker layer of the hydrogel base.

 Methods for incorporating a drug into hydrogels are well known to those skilled in the art and are described, for example, in S.U. Kim and others, "Pharmacological research", N 9, p. 283-290, 1992

 In a preferred embodiment of the device according to the invention, the drug is homogeneously distributed in a hydrogel base with cross-links provided.

 Depending on how the drug is loaded, the hydrogel bases can be formulated as capsules, tablets, films, microspheres, or the like. Compositions formulated using hydrogel bases may include conventional pharmaceutical carriers or excipients, adjuvants, and so on.

 The device according to the invention may contain more than one drug, for example, the device may contain one drug with a high molecular weight in the cavity of the hydrogel base, and another drug with a lower molecular weight, homogeneously distributed in the base.

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

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

The method according to the invention includes:
a) dissolving the decomposable dextranase polymer in a solvent,
b) adding a crosslinking agent capable of crosslinking the polymer with covalent bonds with the solution,
c) allowing the crosslinking agent to react with the degradable dextranase polymer to provide a crosslinked hydrogel base.

 The drug can be loaded into the device before the end of the crosslinking reaction by using several methods. These methods are also well known to those skilled in the art and are described as an example in C.3. Song et al. In the journal Pharmacology, N 70, pp. 216-219, 1981

In a preferred embodiment, the drug is loaded into the device after completion of the crosslinking reaction using the following steps:
a) the hydrogel base is dried, preferably to a water content below 30% by weight and, in particular, below 10% by weight,
b) the dried hydrogel base is brought into contact with a liquid drug or drug solution and allowed to swell,
c) if necessary, the hydrogel is dried.

 This latter method provides a simple and easy method of manufacturing a device according to the invention, with which the drug is dispersed homogeneously.

 A number of examples are provided to further describe the invention.

 FIG. 1 is a graph illustrating the degree of equilibrium of swelling of a device according to the invention as a function of dimethyl sulfoxide content.

 FIG. 2 is a graph illustrating the degree of equilibrium of the swelling of the device of the invention as a function of the content of crosslinking agents.

 FIG. 3 is a graph illustrating the degree of equilibrium of the swelling of the device of the invention as a function of the molecular weight of dextran.

 FIG. 4 is a graph illustrating cleavage in the cecum and stomach, respectively, of the device according to the invention versus time.

 FIG. 5 illustrates the release characteristics of hydrocortisone from the device of the invention.

 Example 1. The preparation of decomposable Dextran hydrogels.

 1.5 grams (9.25 mmol of glucose elements) of dextran 70 (molecular weight 70,000 commercially available in pharmacies) was dissolved in 8.5 ml (85% by volume) of anhydrous dimethyl sulfoxide (DMSO). Directly upon dissolution of dextran, 86 μl (0.46 mmol ~ 5% by molecular weight) of a clear, slightly viscous solution of hexamethylene diisocyanate (ND1, crosslinking agent) was added.

 This was done in a carefully dried glass bowl, since even small amounts of water impede cross-linking reactions. The solution was transferred using a needle and syringe into the form of chemical interaction for the manufacture of films. The mold consists of two Teflon-coated aluminum blocks and water jackets, the solution being placed between the blocks.

By controlling the distance between the blocks using a cushion ring, the thickness of the resulting hydrogel film can be controlled. The temperature was set at 70 ^° C. The crosslinking reaction took place at this temperature for 24 hours.

 Four other hydrogels containing Dextran 70 and various amounts of ND1 and DMSO were synthesized in a similar manner. Two gels had 2.5% and 10% by molecular weight ND1, and two had 80% and 90% by volume DMSO.

 In addition, the molecular weight of dextran was changed. Hydrogels with dextran 10, 500, and 2000 were made (molecular weights 10,000, 500,000, and 2,000,000, respectively).

Table 1 shows a diagram of the synthesized hydrogels (see end of description)
% by volume was calculated relative to the volume of the resulting reactive mixture,% by molecular weight was calculated based on the molar content of glucose in the amount of dextran used.

 Example 2. Determination of the degree of equilibrium swelling of biodegradable dextran hydrogels.

Investigated the degree of equilibrium swelling of the hydrogels prepared in accordance with example 1, samples AG. Three circles were cut from each hydrogel and the weight of the water-swollen gel and DMSO was measured. The gels were washed in water and dried at room temperature for 2 days and in vacuum at a temperature of 40-50 ^o C for 2 days. The degree of equilibrium of the swelling was calculated as the ratio of the mass of the swollen gel to the mass of the dry gel.

 FIG. 1 illustrates the dependence of the degree of equilibrium of swelling of hydrogels containing different amounts of DMSO in the reaction mixture. The increasing amount of DMSO in the reaction mixture leads to an increase in the degree of equilibrium of the swelling resulting from the hydrogel. This is more pronounced in DMSO than in water.

 In FIG. Figure 2 shows that the degree of equilibrium of swelling decreases with an increase in the crosslinking density of the hydrogel.

 From FIG. 3, it can be seen that if the molecular weight of dextran changes, this does not have any significant effect on the degree of equilibrium of the swelling.

 The degree of equilibrium of swelling is higher in DMSO than in water. Thus, DMSO provides a good example of a possible medium for loading a drug into hydrogels.

 Example 3. Assessment of the ability to decompose hydrogels outside the body.

We studied the ability to decompose hydrogels outside the body using dextranase (50 thousand units of dextranase per gram). Discs of hydrogel films with a diameter of 5 mm and a thickness of 1.6 mm prepared as described in Example 1 were cut out and swelled to equilibrium in a 0.1 molar acetate buffer solution with a hydrogen index of 5.4. After reaching equilibrium of swelling, the disks were placed in an enzyme mixture consisting of 1 ml of a 0.1-molar acetate buffer solution with a hydrogen index of 5.4 and 0.5, 3, and 12 μl of dextranase. The mixture was kept in a water bath at 37 ^° C, and the time τ required for complete dissolution of the disks was recorded. The destruction of the gels was monitored by decreasing thickness.

 Table 2 (see the end of the description) shows the time (τ for different gels, when the enzyme mixture consisted of 12 μl of dextranase per ml of buffer solution. With an increase in the crosslink density, the time τ increased and, thus, the degradability was reduced. This also refers to the degree of equilibrium of swelling, the higher the degree of swelling, the higher the degradability of the hydrogel .. However, the results also showed that structural factors also influence the degradation of hydrogels.

 Table 3 shows that with an increase in the amount of dextranase, the destruction rate increases (see the end of the description).

 Example 4. Assessment of the ability to decompose hydrogels in the body.

 The dry weight of 6 samples of hydrogel disks B with a diameter of 5 mm was recorded, and the disks were preliminarily swelled in a buffer isotonic potassium phosphate solution with a hydrogen index of 7.4. Each disc was placed in a gauze bag. Gauze bags were implanted into the stomach and cecum of male SD rats (200-300 g) and attached to the intestinal wall to prevent the release of gels.

 The rats were then given water and food as desired. At different time intervals (1, 2, and 3 days), the rats were sacrificed and gels were removed. The gels were washed in DMSO and water and then dried. Dry weight was recorded and gel breakdown was determined as% degradation (dry weight loss as a percentage of the initial dry weight). The initial dry weight was between 42 and 45 mg.

 In FIG. 4 shows that the gel implanted in the cecum was destroyed after 3 days, while the gel implanted in the stomach was not destroyed. This shows that the destruction of gels occurs in the body and that it occurs in the cecum, and not in the stomach.

 Example 5. Download and allocation of hydrocortisone outside the body.

Hydrogel disks prepared as described in Example 1 with a diameter of 5 mm and a thickness of 1.6 mm (sample B) were washed in water and dried. After drying, the disks were immersed in a hydrocortisone drug solution in DMSO (72.5 mg / ml). After 24 hours, the gels were dried in vacuum at a temperature of 50 ^o C for 2 days. The isolation of hydrocortisone from disks was studied in a 0.1-molar acetate buffer solution with a hydrogen index of 5.4 with and without dextranase (24 μl of dextranase per ml of buffer solution).

The gel was immersed in 5 ml of isolation medium and kept in a water bath at a temperature of 37 ^o C. At time intervals of eight minutes with enzymes and thirty minutes without enzymes, 2.5 ml samples were taken and replaced with fresh medium. The amount of hydrocortisone isolated was determined using the reverse phase HPLC (high performance liquid chromatography) in a C-18 column with a metallon to water ratio of 60:40 as the mobile phase, with ultraviolet determination at a wavelength of 242 nm and an injection volume of 20 μl.

 After 30 minutes, 0.72 mg of hydrocortisone was released from a gel immersed in an enzyme-containing buffer solution, compared with 0.11 mg from a gel in a pure buffer solution. This shows that excretion is greatly increased in the presence of dextranases.

 In FIG. 5 shows the characteristics of the release of hydrocortisone from hydrogels. A faster release of hydrocortisone is obtained when dextranase is present in the isolation medium.

Claims (9)

 1. A device for oral administration of a drug acting in the large intestine, characterized in that said drug is in or surrounded by a hydrogel polymer base, and this base is obtained by reacting dextran or its derivatives with a cross-linking agent, which provides cross-linking bonds system with a covalent bond between the polymer chains.  2. The device according to claim 1, characterized in that the dextran derivative is sulfated, alkoxylated, oxidized or esterified dextran.  3. The device according to claim 1 or 2, characterized in that the dextran and its derivative have a mole. m. 10,000 - 2,000,000 g / mol, preferably 40,000 - 2,000,000 g / mol, in particular 70,000 - 500,000 g / mol.  4. The device according to paragraphs. 1 to 4, characterized in that the cross-linking agent is an urethane bond forming agent.  5. The device according to claim 4, characterized in that the agent forming the urethane bonds is hexamethylenediisocyanate or 1,4-phenylenediisocyanate.  6. The device according to claims 1 to 5, characterized in that the amount of crosslinking agent is 0.05 - 25% by weight of the polymer base.  7. The device according to claims 1 to 6, characterized in that the drug is homogeneously dispersed in a hydrogel polymer base.  8. A method of manufacturing a device for oral administration of a drug acting in the large intestine, described in claims 1 to 7, comprising dissolving the polymer, adding cross-linking agent to the resulting solution, interacting to cross-link the polymer chains and administering drug before or after the end of this interaction.  9. The method of claim 8, in which after the interaction of the polymer with the cross-linking agent, the resulting gel is pre-dried, and then the drug is loaded in the form of a solution or liquid for its absorption by the gel.

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