FIELD OF INVENTION
The present invention relates to pH responsive polymers, which can be used as a coating material for preferential delivery of drugs to the colon.
Background of the Invention
Targeted drug delivery relies on the identification and exploitation of a characteristic that is specific to the target organ. Precise colon targeting requires that the triggering mechanism in the delivery system only responds to the physiological conditions particular to the colon. In the context of colonic targeting, the exploitable gastrointestinal features include pH, transit time, pressure and bacteria. Research interest in the areas of colonic drug delivery has been fuelled by the need to better treat pathologies of the colon that range in seriousness from constipation and diarrhoea to the debilitating inflammatory bowel diseases (ulcerative colitis and Crohn's disease) through to colon carcinoma the third most prevalent form of cancer in both men and women.
The rationale behind targeted drug delivery is to achieve more effective therapies while eliminating the potential for both under-and overdosing. Other advantages of using targeted-delivery systems can include the maintenance of drug levels within a desired range, the need for fewer administrations, optimal use of the drug in question, and increased patient compliance. Targeted drug delivery to the colon would ensure
direct treatment at the disease site and a reduction in systemic side effects. Colon-specific drug-delivery systems offer several potential therapeutic advantages. The colon is attracting attention as a site where poorly absorbed drug molecule may have an enhanced bioavailability. This region of the GIT is recognized as having a somewhat less hostile environment with less diversity and intensity of enzymatic activity than the stomach and the small intestine. Additionally, the colon has a longer retention time and appears highly responsive to agents that enhance the absorption of poorly absorbed drugs. Colon has been targeted to deliver drugs, not only for curing local colonic diseases like colorectal cancer and Crohn's disease, but also more recently colon has been investigated as a potential absorption site for peptides and proteins. In fact oral delivery of peptides and proteins has been acknowledged as one of the most challenging areas of research in targeted drug delivery.
Various pharmaceutical approaches have been exploited for the development of colon targeted drug delivery systems. Bacteria responsive delivery systems employ substrates that are degraded specifically by the micro flora found only in the colonic region. The first such commerically available system to treat ulcerative colitis patients was sulphasalazine (Khan et al. 1977), which is metabolized to 5-ASA and sulphapyridine; 5-ASA is well absorbed from the small intestine, but when administered as a prodrug is released in the colon, where the azo bond undergoes reduction by azoreductases liberating the active ingredient at the site of inflammation. Saffran et al (1986), utilized this principle to develop azo polymers (polymers cross linked with azo aromatic groups) to coat pellets and deliver insulin and vasopressin to rat colon. Another system
disclosed in US Patent No. 5415864, (Kopecek et al. 1995} based on cross linked hydrogels containing azo bonds and exhibiting pH dependent swelling has been developed for colonic targeting of oral dosage forms. Selective drug release in the colon occurs by combination of pH dependent swelling of the hydrogel and degration of hydrogel by enzymatic cleavage of azo bonds by azoredutases. This hydrogel imbibes at least 10% more water at the pH found in the human colon than at the pH found in the human stomach. Kopecek's system is however, not ideal for colonic targeting of drugs, especially peptides, because the hydrogel exhibits certain degree of swelling in the acidic conditions of stomach. Therefore the hydrogel formulation is expected to exhibit considerable swelling before the formulation reaches the colon.
The use of bacteria responsive approach is not without its disadvantages. The release of the drug depends on the presence of colonic anaerobic bacteria. Since the flora of the anaerobic bacteria in the colon is variable, these polymers provide inconsistent drug delivery to colon. Moreover, the use of azo polymers has so far been hindered as some azo aromatic compounds are known to be potential carcinogens. Also, prodrugs being new chemical entities are subject to stringent regulations as their safety, as coating materials is not completely established.
Time dependent dosage forms are formulated to release their drug load after a predetermined lag time. It has been suggested that colonic targeting can be achieved by incorporating a lag time from mouth to colon. A lag time of 5 hours is considered sufficient. Number of systems utilizing this concept has been developed. An oral delivery system based
on a time dependent explosion mechanism is described by Ueda et al (US Patent No. 4871549, 1989) The formulations described by Ueda et al represent a core of active ingredient and swelling agents encased by a single insoluble membrane. When this formulation is exposed to gastrointestinal fluid, the core swells and eventually bursts the encasing membrane, leading to drug release. A somewhat complex device, PulsincapR was proposed by Wilding et al (1992). This device comprises a non-disintegrating half capsule shell sealed at the open end with a hydrogel plug. The plug hydrates when comes in contact with gastrointestinal fluid and swells to an extent that it is expelled from the capsule body releasing the drug. Another delivery system disclosed in US Patent No. 6039975 (Shah et al, 2000) is designed to release the drug consistently in the colon by a time dependent explosion mechanism. The delivery system in this case is a tablet, comprising three parts; an outer enteric coating, an inner semi permeable polymer membrane containing a plasticizer and a central core comprising swelling excipients and an active ingredient. The outer enteric coating, which encases the membrane, dissolves at about pH 5.5, which exposes the semi permeable membrane to the small intestinal fluids. The swelling of the central core causes the membrane to burst after 4-6 hours of exposure to small intestinal fluids.
The design of a time responsive colonic delivery system is reliant on the consistency of the gastric emptying times. Contrary to popular belief, small intestinal transit is subject to considerable inter subject variability. Hebdent et al (1999) have reported variable release positions from a
PulsincapR device, due to variability in gastric emptying. Another disadvantage associated with time responsive delivery device is a distinct lack of spread of the drug from the tablet/capsule after ejection of the plug (in case of PulsincapR) or disintegration of the outer membrane (in case of Ueda et al or Shah et al). This clearly limits the time responsive approach for colonic delivery.
The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the gastrointestinal tract. There is a pH gradient in the gastrointestinal tract with values ranging from 1-3 in the stomach through 5 in the proximal small intestine to about 7 at the illeocecal junction and increases to a maximum of 8 through the transverse and descending colon.
This pH differential between the stomach and small intestine has historically been exploited to deliver drugs to the small intestine by the way of pH responsive enteric coatings. These polymer coatings are resistant to the acidic conditions of the stomach but ionize and dissolve above a certain threshold pH found in the small intestine. Thus it is also possible to apply this concept to deliver drugs to the colon by use of coating materials with a relatively high threshold dissolution pH. During the last two decades therapeutic systems based on such enteric coatings have been developed and commercialized.
The design of the polymer, to be utilized in targeted/controlled delivery devices, depends on consideration of characteristics like route of administration and the target site. In order to exploit the pH gradient in the gastrointestinal tract to deliver pharmaceutically active ingredient specifically to the colonic region, reliable coatings soluble as a function of environmental pH value have to be utilized. The advantage of utilizing the pH responsive approach for colonic delivery is the ease with which these polymers can be fabricated. Moreover these polymers have the benefit that they can be processed with high degree of reproducibility.
Dew et al (Clin. Pharmacol. 14: 405-408, 1982) employed the concept of enteric coating to target drugs to the colon. Dew et al reported the use of an acrylic based resin (available under the Registered Trade Mark Eudragit S) to coat 5-amino salicylic acid or steroids as a means to deliver these drugs to the colon. Eudragit S is the most commonly utilized polymer for this purpose. It is an anionic copolymer of methacrylic acid and methyl methacrylate in which the ratio of the carboxylic acid to ester functionality is 1:2 and has a mean molecular weight of 135000. It is resistant to the acidic conditions of the stomach but dissolves slowly in the intestinal juice. Another copolymer in which the ratio of the carboxylic to ester functionally is 1:1 (available under the Registered Trade Mark Eudragit L) is readily soluble in the intestinal juice.
In order to achieve desirable solubility and precise delivery to colon commercially available polymers are admixed in various proportions. An important observation in the present context has been made by Rhodes, et al., U.S. Pat. No. 5,541,171 (1996) that Eudragit S is usually employed in admixture with Eudragit L and these mixtures invariably dissolve below pH 7.
The systems developed so far, for targeted delivery to the colon, which utilize the concept of enteric coating to protect the active pharmaceutical ingredient from premature release in the upper gastrointestinal tract use either a combination of polymers in a particular ratio or require the application of more than one layers in order to achieve precise and predictable delivery of the drug only to the colon. The said layers may be of different polymer constituting a "multi-layered" system.
Thus, there is a need for a better coating material with a higher threshold dissolution pH than those of commercially available materials and which will release the active ingredient only in the colon and moreover complies with the specific active ingredient release profile.
Objects of the invention
The object of this invention is to provide a pH responsive polymer, which can be used as a coating material for micro/macro capsules/particles containing the drug, useful for treating colonic disorders, and delivering the major amount of the drug preferentially to the colon.
Another objective of this invention is to provide a pH responsive polymer, which can provide an orally administrable pharmaceutical dosage form, which releases virtually no active component in the stomach and enables the release of the active ingredient in the colon showing no premature release.
Yet another object of this invention is to provide a pH responsive polymer that degrades in the colon, thus delivering the drug at the target site, i.e. colon.
Another object of this invention is to provide a pH responsive polymer that can serve as an oral carrier for peptide/protein drugs and deliver them specifically to the colon. The proteolytic enzymes present in high concentration in the stomach and small intestine rapidly degrade such drugs.
Accordingly the present invention have endeavored to develop a novel pH responsive polymer possessing all the required characteristics of the material, i.e. high threshold dissolution pH and biocompatibility, which can be utilized to coat micro /macro capsules, particles intended for colonic delivery.
Description of the Invention
The above said pH responsive polymer is a acrylic copolymer which can be used as coating material for micro/macro capsules, particles intended for delivering drugs preferentially to the colon, without releasing the pharmaceutically active component in the stomach or in the small intestine.
The composition of this alkyl acrylic acid-alkyl acrylate copolymer is based on controlling the percentage weight of the ester component. The threshold dissolution pH of the resulting copolymer can be adjusted to achieve delivery of the drug to the desired region of the colon. The dissolution properties of the said copolymer can be precisely tailored by varying its composition.
The copolymer of the present invention may be prepared using methacrylic acid (MA) and its methyl ester methyl methacrylate (MMA) in presence of ammonium persulphate as an initiator
The copolymer of the present invention may be a random copolymer of constituents MA and MAA.
— (-MA+MMA-)m —
wherein,
m is an integer larger than 2, preferably from 3 to 50.
In this copolymer the carboxylic acid moieties are responsible for its pH responsive behavior.
The monomers are not limited to only these two monomers. Any monomers having similar characteristics can be used for such a polymer. As for example, instead of MA one can take alkyl acrylic acid of the general formula
(Formula Removed)
Wherein R1 may be of the general formula CnH2n+i in which n may have any value from 1 to 5.
Instead of MMA one can take alkyl acrylate of the general formula
(Formula Removed)
Wherein R2 may be same as R1 or may be of the general formula CnH2n+i in which n may have any value from 1 to 5 and Ra may be of the general formula CnH2n+i in which n may have any value from 1 to 5.
Among the drugs for which this copolymer will be useful are those used for the treatment of chronic diseases of the bowel, including inflammatory diseases like irritable bowel diseases (IBD) and colorectal cancer. These drugs may include salicylates, sulfonamides, peptides, antibodies, ACE inhibitors, certain glucocorticoids and antichloinergics.
The drug contained in the oral pharmaceutical composition according to the invention may be any drug or medicament known for its therapeutic effect on colonic disease. The amount of the active component that will be included in the composition will vary depending upon the activity of the drug relative to the condition being treated.
The combination of the monomers is preferably MA, MMA in the molar ratio ranging from 1:2.10 to 1:5.00 or 29.06% to 70.94% by weight of MA and 16.22% to 83.78% by weight of MMA.
The inert gas is chosen from nitrogen, argon, etc. or any other inert gas.
Figure 1 comprises a flow diagram depicting the process for the preparation of the copolymer.
Synthesis of copolymer
The monomers, in appropriate weight percentages, are mixed with a solvent system. The mentioned solvent system consists of 75% (v/v) of an organic polar solvent and 25% (v/v) water; pH 4-8.
The organic polar solvent is taken from methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, dichloromethane (DCM) either alone or in mixture.
An inert gas is flushed through the reaction mixture containing the solvent system and the monomers.
An aqueous, saturated solution of the initiator, ammonium persulphate, is then added. The reaction mixture is maintained at 35-65 °C for four to eight hours under inert atmosphere.
The obtained solid material is then purified by dialysis to remove all the toxic monomers and the initiator.
The copolymer so obtained is dried and stored at room temperature.
The copolymer, said above, has a mean molecular mass of about 1650 and shows a melting endotherm at 80.2 and 232.64 °C (Fig.4).
Figure 2 exhibits the FTIR spectra of the monomers and the
copolymer.
Figure 3 exhibits the XRD pattern of the copolymer Figure 4 exhibits the DSC of the copolymer. Figure 5 exhibits the NMR spectrum of the copolymer.
UTILIZING THE POLYMER TO COAT MACRO CAPSULES:
The polymer is dissolved in organic solvents chosen from ethanol, methanol, acetone, isopropyl alcohol, ethyl acetate, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulphoxide (DMSO), dioxane, dichlorome thane.
The coating may be applied to the device carrying the active ingredient by any of the conventional means.
Preferable device on macro scale, said above, is a hard gelatin capsule containing the pharmaceutically active agent, which could be coated with the polymer followed by drying.
The copolymer of the present invention forms a smooth, tough and a flexible coating on the surface of the capsule.
Figure 6 shows the release profile where salicylic acid has been used as a model drug and the ratio of the monomers, MA: MMA, in the copolymer used is 1:3,
No drug release takes place at pH 1 therefore the copolymer is enteric in nature.
At pH 7 only 10% drug release in the initial 2 hours and a maximum of 26% in 6 hours was observed. Only a minimal amount of the drug is released at pH 7 suggesting that no premature drug release would be observed in the illeum or the ileocecal junction.
At pH 7.4 complete drug release was observed in a span of 3 hours. The drug release pattern at pH 7.4 indicates that the copolymer dissolves slowly in the pH range 7-7.4. The rate at which the drug is released, 35% in the first hour, and about 70% in the next one hour, exemplifies the same observation.
At pH 8 complete drug release (about 92%) within 1 hour was observed. The drug release pattern at pH 8 clearly indicates that the copolymer dissolves rapidly at pH 8.
It is to be noted that the present invention is susceptible to modifications, adaptations and changes by those skilled in the art. Such variant embodiments employing the concepts and features of this invention are intended to be within the scope of the present invention, which is further set forth under the following claims: -

WE CLAIM;
1. A process for the preparation of a pH responsive polymer which can
be used as a coating material for micro/macro capsules, particles
intended for delivering drugs preferentially to the colon comprising:
- dissolving monomers in a solvent system, as herein described to
obtain a clear solution,
- flushing an inert gas through the said solution,
- adding an aqueous solution of an initiator,
- subjecting the solution to polymerization in presence of an inert
gas till the polymerization is complete,
- purifying the said copolymer from the toxic monomers and other
unreacted material by dialysis.

2. A process as claimed in claim 1 wherein the monomers are alkyl
acrylic acid and alkyl acrylate having chain length Cl to C5.
3. A process as claimed in claim 1 wherein the combination of the
monomers is preferably, MA and MMA in the molar ratio ranging from
1:2.10 to 1:5.00 or weight percentage ranging from 29.06% to 70.94%
MA and 16.22% to 83.78% MMA.
4. A process as claimed in claim 1 wherein the inert gas is nitrogen or
argon or any other inert gas of the like.
5. A process as claimed in claim 1 wherein the copolymers are
biocompatible materials.
6. A process as claimed in claim 1 wherein the initiator is an aqueous
solution of ammonium persulphate.
7. A process as claimed in claim 1 wherein the aqueous solution is a
saturated solution.
8. A process as claimed in claim 1 wherein the temperature at which the
polymerization is carried is 35-65°C and is carried out for 4-8 hours.
9. A process as claimed in claim 1 wherein the dialysis is carried out for
10-12 hours to eliminate unreacted monomers and initiator.
10. A process for the preparation of a pH responsive polymer
substantially as herein described with reference to, and as illustrated
by, the examples.