PL172724B1 - Therapeutic system and method of obtaining same - 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

The present invention relates to oral therapeutic systems designed to deliver drugs to the colon and comprising a polymeric matrix and the drug contained within or surrounded by the matrix.

a a a a i c J

Many drugs are very sensitive to the action of proteolytic enzymes found in the digestive juices of the stomach and small intestine. Drugs such as peptides and proteins are broken down by the action of proteolytic enzymes, which significantly reduces their absorption.

While oral administration is more convenient and readily acceptable to the patient, the most common method of delivering drugs such as peptides and proteins is by parenteral administration.

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

Thus, it would be very advantageous to find a suitable method for delivering drugs selectively to the colon by administering them via the gastrointestinal tract.

rp, 1 _____ 4ΐ · _ · 5ΐι «<τ, polymeric compounds such as hyurogels are widely used in therapeutic systems designed for controlled release or used as stimulus-sensitive systems. Such systems are described, for example, in Hydrogels in Medicine and Pharmacy, Ed. N.A.Peppes, CRC Press, 1987. The preparations described therein are generally not metabolized. The release of the pharmacologically active agents loaded into these gels is typically controlled by simple diffusion through the system as a function of the water content of the gel. Hence, such gels are not suitable for the release of drugs to specific regions of the intestine when administered by the oral route.

European Patent Application No. 357401 discloses a metabolizable hydrogel matrix composed of a protein, a polysaccharide and a cross-linking agent. However, this composition is not for use by the oral route.

U.S. Patent No. 4,024,073 discloses a hydrogel composition containing a water-soluble polymer containing a chelating agent bound to the polymer chain and a multivalent metal ion cross-linking the polymer molecules through the chelating agent. The hydrogel is useful as a carrier for the rhythmic release of drugs and other medicaments without targeting the colon.

Japanese Patent Nos. 1156912, 62010012, 5721315, German Patent Publication No. 3,400106 and US Patent No. 4,496,553 describe the preparation of compressed tablets for the slow release of drugs using soluble polymers or polysaccharides. All of these tablets are typical time-disintegrating tablets and do not specifically target the colon.

British Patent Application No. 2,066,070 describes a pharmaceutical preparation in the form of a tablet for the release of the active ingredient in the colon. The tablet contains the active ingredient coated with a film of cellulose and its derivatives. This coating is decomposed by the action of bacteria present in the colon. However, a drawback of this system is that the coating may dissolve in the stomach or in the upper gastrointestinal tract. Thus, this patent describes a system that is susceptible to varying changes from individual to individual as it passes through the intestines and that does not selectively release the active ingredient in the colon.

Osmotic therapeutic systems for the delivery of a drug to the colon are described in British Patent Applications Nos. 2,166,051 and 2,166,052. These devices include a laminated membrane surrounding the drug-containing compartment. This membrane deflates the onset of substantial drug release. Such osmotic therapeutic systems suffer from the same disadvantages as the system described in British Patent Application No. 2,066,070.

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A publication relating to the technical field to which the present invention pertains is Kost et al., Chemically-modified polysaccharides for enzymatically-controlled oral drug de-Uvery ’fRiomaterials, 11, 695-698 (1990)]. It describes a system containing ionically cross-linked starch used for the controlled release of macromolecules into the intestines. This system takes advantage of the presence of amylases in the small intestine and therefore is not directed to the release of the drug into the large intestine or into the colon.

More recently, Rubinstein et al. [Pharm. Res., 9, 275-278 (1992)] describe drug release in the colon using a chondroitin matrix. This system consists of a drug embedded in a compressed chondroitin matrix. This matrix can degrade at any time as it travels through the small intestine. Thus, this system is not suited to the site specific of drug delivery to the colon.

WO 92/00732 describes a composition for the delivery of therapeutically active substances by the oral route to the colon. The composition comprises a core matrix with the active ingredient (s) dispersed therein, and an outer coating layer that does not contain any active ingredients. Both the matrix core and the outer coating layer are based on polysaccharides such as pectin and / or dextran which are formed coacervates by cross-linking with a multivalent cation, the cation being divalent or trivalent.

In the stomach of a patient with normal gastric acid function, hydrogen ions penetrate both the outer layer and the core of the composition, and through ion exchange, the hydrogen ions replace the multivalent cations, which causes, to a large extent, the complexation of polysaccharide chains to disappear and the composition to be kept to a greater or lesser extent rather due to spatial effects than cationic bonds.

This means that the composition degrades to a greater or lesser extent on passage through the stomach and small intestine, and that degradation during this passage is highly dependent on the presence of other cations, the average residence time of the composition, and especially on the function of the acids. in the gastro-intestinal tract of the patient himself, in other words, a composition of the above type may prove to be capable of delivering the active ingredient to the colon of a given patient when it is prepared specifically for him. It follows that such a composition cannot be commercially available and suitable for this application.

The use of hydrogels containing metabolizable bonds has been previously described by Rrondsted and Kopecek in Proceed. Intern. Symp. Cóntrol. Rei. Rioact Mater., 18, 345-346 (1991). Hydrogels are characterized by the ability to swell pH-dependent as a result of the incorporation of acid groups into the polymer backbone, as well as undergo metabolism as a result of the sensitivity of the crosslinks to the action of enzymes. This type of system takes advantage of the presence of bacterial azoreductases in the colon. Hydrogels break down after breaking down the cross-links and loosening the polymer backbone.

By using these acidic hydrogels, it is possible to avoid much more degradation and release of the drug in the stomach. However, degradation of the hydrogel, and hence drug release, into the colon appears to occur very slowly and only a fraction of the drug may be released as it travels through the colon.

Colon drug delivery was achieved by the use of dextran prodrugs [Larsen et al., Pharm. Res., 6, 995-999 (1989)], which release the active ingredient after cleavage by bacterial enzymes present only in the colon. The drug was covalently bound to the dextran. Once the prodrug reached the colon, the bacterial dextranases were ready to break down the dextran, releasing the drug upon covalent bond hydrolysis. The disadvantage of this system is the serious problem of high drug burden. In addition, the drug must contain an appropriate functional group that can be modified, and must also be capable of withstanding the experimental conditions adopted for coupling to the dextran carrier.

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As can be seen from this, there is a need for an oral therapeutic system with improved colon selectivity.

It is an object of the present invention to provide such a therapeutic system for the delivery of a drug to the colon, whereby it would be possible to deliver one or more drugs to the colon without substantial loss of the drug in the stomach, small intestine and faeces.

The oral therapeutic system according to the invention, composed of a polymeric matrix and a drug which acts when released in the colon, contained in a matrix or surrounded by a matrix, is characterized in that the polymeric matrix is a matrix made of a cross-linked hydrogel containing a polymer which decomposes under influenced by dextranase and a cross-linking agent that provides for the formation of a network of covalent bonds between the polymer chains, the cross-linking agent being 0.05-25 mole% of the monomer units in the hydrogel.

As mentioned above, dextranases are only found in the colon. In the oral therapeutic system of the present invention, the drug is protected by a ____ a ____ · ___ j____ and a polymer (which breaks apart by the cooling of uextranase) as the system passes through the stomach and small intestine. Upon reaching the colon, the polymeric matrix is degraded by the action of the dextranase and the drug is released.

The rate of degradation of the polymer matrix, and hence drug release, is dependent on various factors, such as the choice of polymer to be degraded by dextranase, the type of cross-linking agent, the degree of cross-linking, the water content of the hydrogel matrix, and the configuration and size of the system when formulated as final. The oral therapeutic system of the invention can be designed such that virtually all of the drug is released in the colon.

The dextranase-degradable polymer present in the therapeutic system of the invention must be substantially resistant to the digestive fluids of the stomach and small intestine.

The polymer which is degraded by the action of dextranase is dextran or modified dextran. A number of ways to modify dextran are known. See, for example: W.M. Meckerman and C.R. Ricketts, Biochem. J., 76, 117-120 (1960) (concerned with the preparation of diethylaminoethyl dextran) and K. Nagasawa et al., Carbohydr. Res., 21, 420-426 (1972) (relates to the synthesis of dextran sulfate).

Due to the use of modified dextran instead of ordinary dextran, it became possible to obtain a hydrogel matrix with a more hydrophobic or more hydrophilic, as well as charged character. It can be used to adjust the swelling properties of the hydrogel matrix. Also, the dextranase degradable polymer is selected according to the type of drug to be incorporated into the hydrogel matrix such that the polymer does not react with the drug in a manner that irreversibly inactivates the drug.

Sulphated dextran, alkoxylated dextran, oxidized dextran and esterified dextran are particularly preferred.

The dextranase-degraded polymer may have a molecular weight in the range of 10,000 to 2,000,000, preferably in the range of 4,000 to 2,000,000.

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 capable of providing a network bond to the polymer structure. The polymer can maintain its integrity due to the presence of covalent bonds such as a urethane, ester, ether, amide, carbonate or carbamate bond. Preferred crosslinking agents are diisocyanates which provide urethane linkages, such as hexamethylene diisocyanate and 1,4-phenylenediisocyanate.

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The degree of cross-linking of the hydrogel, as well as the hydrogel composition itself, affects the degradation kinetics, loading, and overall anxiety release profile from the matrix. This means that a higher degree of cross-linking generally will lead to a slower degradation of i

U w -L O i V u O s lłi m Ιό ·, n p -p <\ sń nrrry c> i + z-4 zt «· <-» ».1f V» - »^ 4 ·. ·.

puur ^ u xu. ^ asy αιυρινπ uoiwiuwama piuwcuri uu wómciu and release.

Of course, the effect of the degree of cross-linking on drug release depends on the molecular size of the drug and the manner in which it is introduced into the therapeutic system. Preferably, the crosslinker comprises 0.05-25 mole% of monomer units in the hydrogel.

In principle, any type of drug may be used as a medicament. The therapeutic system according to the invention is particularly preferably used when administering drugs intended for the treatment of diseases that have the habitat of the colon. These include, for example, drugs such as steroids, 5-amino-salicylic acid, anti-inflammatory agents, anti-cancer drugs, an enzyme agent, and bacterial cultures. It is also advantageous to use the therapeutic system of the invention for the administration of unstable drugs in the stomach and / or small intestine, such as, for example, peptides such as insulin, vasopressin or growth hormones, proteins, enzymes and vaccines.

The therapeutic system of the invention is also advantageous in terms of delayed administration of drugs.

By using the therapeutic system of the invention, drugs such as rheumatism and other analgesics can be administered to the patient before falling asleep and may be effective in the morning since the time required for the therapeutic system to reach the colon is approximately 8 hours.

The drug can be incorporated into the hyrogel matrix in a variety of ways. For example, the drug or drug-containing gelatin capsule may be covered with a hydrogel matrix, or the drug may be contained in the lumen of the hydrogel pattern, i.e. the drug is surrounded by a thicker layer of hydrogel matrix.

Methods for incorporating medicament into hydrogels are well known and are within the knowledge of one skilled in the art. They are described, for example, by S.W. Kim et al. in Pharm. Res., 9, 283-290 (1992).

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

Depending on the manner in which the drug is introduced, the hydrogel matrices may be formed into capsules, tablets, films, microspheres, etc. Compositions formulated using hydrogel matrices may contain conventional pharmaceutical carriers or excipients, adjuvants, etc.

The therapeutic system of the invention may contain more than one drug. For example, the therapeutic system may contain one drug, having a high molecular weight in the lumen of the hydrogel matrix, and a second drug, having a lower molecular weight, may be uniformly dispersed throughout the matrix.

It will be obvious to a person skilled in the art that other combinations are also possible, with the content of the drugs released in the stomach or in the small intestine.

Another object of the invention is to provide a method for the manufacture of a therapeutic system according to the invention. A method for the preparation of an oral therapeutic smear composed of a polymeric matrix and a drug acting after release in the colon, contained in a matrix or surrounded by a matrix, wherein the polymeric matrix is a matrix made of a cross-linked hydrogel containing a dextranase-degradable polymer and an agent. cross-linking, ensuring the formation of a network of covalent bonds between the polymer chains, the cross-linking agent being 0.05-25 mole% of monomer units in the hydrogel, characterized in that it comprises:

a) dissolving the polymer which is decomposed by dextranase in a solvent,

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b) adding a cross-linking agent to the solution, capable of cross-linking the polymer with covalent bonds,

c) allowing the reaction of the crosslinker with the polymer undergoing rozpłaHnun nnd u ^ kntrAm action nłwnreAkia ηκΗτνπν σ πτΐαρΐητιo LL of ^Τ χ ^ν · U ^ AIUUAAIU UL UUUrj In W1U UL · WW! <jVH1U nm><0> Hydrogel and drug introduction from said solution before or after completion of the reaction between the polymer and the cross-linking agent.

Preferably, the drug is incorporated into the polymer and the cross-linking agent before the cross-linking reaction is complete, after which the cross-linking reaction is allowed to complete.

Also preferably, a drug solution or drug in liquid form is incorporated into a cross-linked hydrogel, where the pre-dried hydrogel absorbs the drug.

The drug may be introduced into the system prior to the completion of the cross-linking reaction by a variety of methods. These methods also fall within the scope of the ordinary knowledge of those skilled in the art and are described, for example, by S.Z. Songa et al. in J. Pharm. Sci., 70, 216-219 (1981).

In a preferred embodiment, the drug is introduced into the system after the cross-linking reaction is complete by carrying out the following step

a) the hydrogel matrix is subjected to predrying, preferably to a water content of less than 30% by weight, in particular less than 10% by weight,

b) the dried hydrogel matrix is brought into contact with a liquid drug or drug solution and allowed to swell,

c) if desired, the hydrogel is dried.

This method provides a very simple and easy way to manufacture the system of the invention, whereby the drug is dispersed homogeneously.

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

Fig. 1 is a graph showing the degree of swelling equilibrium for the therapeutic system of the invention depending on the DMSO content.

Fig. 2 is a graph showing the degree of swelling equilibrium for the therapeutic system of the invention as a function of the content of cross-linking agents.

Fig. 3 is a graph showing the degree of swelling equilibrium for the therapeutic system of the invention as a function of the molecular weight of the dextran.

Fig. 4 is a graph showing the distribution of a therapeutic system according to the invention in the caecum and stomach, respectively, as a function of time.

Figure 5 shows the release profiles of hydrocortisone from the therapeutic system of the invention.

Example I. Preparation of metabolizable dextran hydrogels,

1.5 g (9.25 mmol glucose units) of dextran 70 (MW 70,000, commercially available from Pharmacia) was dissolved in 8.5 ml (85% v / v) anhydrous dimethyl sulfoxide (DMSO). Immediately after the dextran had dissolved to form a clear, slightly viscous solution, 86 µL (0.46 mmol, about 5 mol%) of hexamethylene diisocyanate (HDI, crosslinker) was added. This was done in a carefully dried glass vessel, since the cross-linking reaction is stopped in the presence of even traces of water. The solution was transferred to a reaction mold for film preparation using a needle and syringe. This mold consists of two water-jacketed and Teflon-coated aluminum bars between which the solution is introduced. By adjusting the distance between these bars using a spacer ring, it is possible to control the thickness of the hydrogel film produced. The temperature was set to 70 ° C. The cross-linking reaction took place at this temperature for 24 hours.

Four other hydrogels containing dextran 70 and varying amounts of HDI and DMSO were synthesized in a similar manner. Two gels contained 2.5 and 10 mole% HDI, and two contained 80 and 90 vol. DMSO.

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The molecular weight of the dextran also varied. Thus, hydrogels were produced with dextran of 10, 500 and 2,000 (molecular weight 10,000, 500,000 and 2,000,000, respectively).

Table 1 shows the system of the synthesized hydrogels.

Table 1

A sample Dextran (molecular mtusa) DMSO (% vol) HDI (% mol) AND 70,000 85 2.5 10,000 o t ~ B 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

% vol was calculated relative to the volume of the resulting reaction mixture.

The mole% was calculated from the glucose content (in moles) of the total amount of dextran used.

Example II. Determination of the degree of equilibrium swelling of metabolizable dextran hydrogels.

The degree of equilibrium swelling of the hydrogels prepared as described in Example 1 (samples A - G) was investigated. Three discs were cut from each hydrogel and the weight of the swollen gel in water and DMSO was measured. The gels were washed with water and dried at room temperature for 2 days and under vacuum at 40-50 ° C for 2 days. The degree of swelling equilibrium was determined as the ratio of the weight of the swollen gel to the weight of the dry gel.

Figure 1 shows the ratio of the degree of equilibrium 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 equilibrium degree of swelling of the hydrogel formed. This is more evident for DMSO than for water.

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

From Figure 3, it can be seen that the degree of swelling equilibrium is not substantially affected by the change in the molecular weight of the dextran.

The degree of equilibrium swelling is greater in DMSO than in water. Hence, DMSO appears to be a good example of a possible agent for drug incorporation into hydration.

Example III. In vitro evaluation of hydrogels degradability.

In vitro, the degradability of hydrogels was tested with dextranase (50,000 dextranase units / g). Discs 5 mm in diameter and 1.6 mm thick were cut from the hydrogel membranes prepared as described in Example 1. These discs were allowed to swell to equilibrium in 0.1 M acetate buffer,

172 724 pH 5.4. After swelling equilibrated, the discs were transferred to enzyme mixtures consisting of 1 ml of 0.1 M acetate buffer, pH 5.4 and 0.5 or 3 or 12 l of dextranase. Each mixture was incubated in a water bath at 37 ° C.

rrz · vcxi λ. in rv and iCjCói-iUWiiiiU GZtio t pOtrZCbliy ÓO and the thickness of the gel was monitored by the thickness of the discs.

Table 2 shows the r values for different gels in the case where the enzyme mixture consists of 12 / * 1 dextranase / ml buffer. As the cross-link density increases, the r-value increases and hence degradability decreases. This also applies to the degree of equilibrium of the swelling; the higher the degree of swelling, the greater the degradability of the hydrogel. However, the obtained results indicate that also structural factors influence the degradability of hydrogels.

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

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Table 2

A sample T (min) AND 18 ί 1.5 B 36 ± 4.6 C. 60 + 4.9 B 255 4 15 £ 46 4 1 P. 46 ± 2 G. 33 ± 0.6

Table 3

A sample The amount of dextranase (Λ1) (min) B 0.5 157 ± 5.3 B 3 131 and 14.8 B 12 36 ± 4.6

Example IV. In vivo evaluation of degradability.

The dry weight of six hydrogel samples B was recorded in the form of 5 mm diameter discs, and the discs were placed for pre-swelling in isotonic phosphate buffer, pH 7.4. Each disc was placed in a gauze bag. These pouches were then implanted into the stomach and cecum of male DS rats (200-300 g), attached to the intestinal wall to prevent excretion of the gels. The rats were then provided with water and food ad libitum. At various time intervals (namely after 1, 2 and 3 days) the rats were sacrificed and the gels removed. The gels were washed in DMSO and water and then dried. The dry weight was recorded and the degradation of the gels was assessed, expressing the results as% degradation (weight loss of dry substances in% of the initial dry weight). The initial weight of the dry substance ranged from 42 to 45 mg.

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Figure 4 shows that after 3 days the gels implanted in the cecum have degraded, while the gels implanted in the stomach have not degraded. This points to the fact. that the degradation of gels takes place in vivo, and that it takes place in the caecum and not in

Example 5 Introduction and in vitro release of hydrocortisone.

The hydrogel discs obtained as described in Example 1, 5 mm in diameter and 1.6 mm in thickness (sample B), were washed with water and dried. After drying, the discs were immersed in a solution of the drug, namely hydrocortisone, in DMSO (72.5 mg / ml). After 24 hours, the gels were dried in vacuo at 50 ° C for 2 days. The study of hydrocortisone release from the discs was performed in 0.1 M acetate buffer, pH 5.4, with dextranase (24 μΐ dextranase / ml buffer) or in the absence of dextranase. The gel was immersed in 5 ml of the release medium and kept in a water bath at 37 ° C. At eighth minute, when enzymes were present, and at 30th minute, when enzymes were no longer present, 2.5 ml samples were taken and replaced with fresh medium. The amount of released hywufiunyiunu uounuŁuuu λ uuwiutuuugu imnu na kujuuuho ό-io, l using methanol: water 6θ: 40 as the mobile phase. UV detection at 242 nm, injection volume 20 μl.

After 30 minutes, 0.72 mg of hydrocortisone was released from the gel immersed in the enzyme buffer, while 0.11 mg of hydrocortisone was released from the gel immersed in pure buffer. This shows that in the presence of dextranase, drug release increases drastically.

Figure 5 shows the release profiles of hydrocortisone from hydrogels. Much faster release of hydrocortisone is achieved when dextranase is present in the release medium.

Claims (9)

Patent claims CLAIMS 1. An oral therapeutic system composed of a polymeric matrix and a drug, acting upon release in the colon, contained within or surrounded by the matrix, characterized in that the polymeric matrix is a matrix made of a cross-linked hydrogel containing dextran as dextranase degradable polymer and a cross-linking agent ensuring the formation of a network of covalent bonds between the polymer chains, the cross-linking agent being 0.05-25 mole% of monomer units in the hydrogel. 2. The therapeutic system according to claim 1, The process of claim 1, wherein the dextran is in the form of sulfate, alkoxylated dextran, oxidized dextran or esterified dextran. 3. The therapeutic system according to claim 1, The process of claim 1, wherein the dextran degradable polymer has a molecular weight in the range from 10,000 to 2,000,000, preferably in the range from 40,000 to 2,000,000 and especially in the range from 70,000 to 500,000. 4. The therapeutic system according to claim 1, The process of claim 1, wherein the crosslinking agent is a urethane bond former. 5. The therapeutic system according to claim 1, The process of claim 4, wherein the urethane bonding agent is hexamethylene diisocyanate or 1,4-phenylenediisocyanate. 6. The therapeutic system according to claim 1, The method of claim 1, wherein the drug is homogeneously dispersed in the hydrogel matrix. 7. A method for producing an oral therapeutic system comprised of a polymeric matrix and a drug which is released in the colon and contained within or surrounded by the matrix, the polymeric matrix being a matrix made of a cross-linked hydrogel containing a dextranase-degradable polymer and a cross-linking agent. , providing for the formation of a network of covalent bonds between the polymer chains, the cross-linking agent representing 0.05-25 mole% of monomeric units in the hydrogel, characterized in that it comprises a) dissolving the polymer decomposed by dextranase in a solvent, b) adding a cross-linking agent to the solution, capable of cross-linking the polymer with covalent bonds, c) allowing the cross-linking agent to react with the polymer which is decomposed by dextranase treatment to form a cross-linked hydrogel matrix and introducing the drug into said solution before or after completion of the reaction between the polymer and the cross-linking agent. 8. The method according to p. The process of claim 7, wherein the drug is incorporated into the polymer and crosslinker before the crosslinking reaction is complete, and then the crosslinking reaction is allowed to complete. 9. The method according to p. The method of claim 7, wherein the drug solution or drug in liquid form is incorporated into a cross-linked hydrogel, wherein the pre-dried hydrogel absorbs the drug.