Polymer based formulation for release of drugs and bioactives at specific GIT sites

Abstract

The present invention is related to polymer based formulation for release of drugs and bioactives at gastrointestinal tract specific sites including stomach, intestine and colon.

Claims

1. A polymer capsule for delivery of an active pharmaceutical ingredient (API) consisting of: a shell formed of a plurality of layers from a dried solution of from 0.01 to 10% w/v of at least one polymer selected from HPMC, CMC, PVA, starch or a combination thereof, and from 2-6% w/v of sodium alginate cross-linked with from 0.025 to 18% w/v of bivalent ions, trivalent ions or a combination thereof, the remainder with water, wherein the capsule contains the API inside the capsule, and wherein the capsule prevents release of the API in the acid environment of the stomach.

2. The polymer capsule of claim 1, wherein the polymer capsule is delivered as immediate drug release, extended-drug release, sustained-drug release, lag-drug release, pulsatile-drug release, delayed-drug release, modified drug release, or any combinations of profiles at a specific time and site.

3. The polymer capsule of claim 2, wherein the API is formulated into a form selected from the group consisting of powder, pellets, enteric-coated granules, and tablets.

4. The polymer capsule of claim 1, wherein the API is selected from a group consisting of water-soluble, water-insoluble, acid-labile, non-acid labile, proteins and peptides.

5. The polymer capsule of claim 1, wherein the said polymer is cross-linked with bi- and/or trivalent ions in the form of their salts.

6. A method of treating irritable bowel disease or cancer, the method comprising providing the polymer capsule of claim 1, including a therapeutically effective amount of an API for treating irritable bowel disease or cancer disposed therein, and administering the API-containing polymer capsule to a patient in need thereof, wherein the API is delivered to the colon and is effective for the treatment of irritable bowel disease or cancer.

Description

BRIEF DESCRIPTION OF FIGURES

(1) FIG. 1. Schematic for preparation of capsule dosage form comprising polymer and ions and the Dimensions of drug releasing polymer capsule using multi ions of alginate gel.

(2) FIG. 2. Varied release profiles of APIs with alginate and/or bi- or trivalent ions and/or polymers.

(3) FIG. 3. Dissolution profile of H.sup.+ proton pump inhibitor Omeprazole—a pH unstable API.

(4) FIG. 4. Dissolution profile of Metformin Hydrochloride showing Immediate Release (IR) Profile.

(5) FIG. 5. Dissolution profile of Metoprolol tartrate in 0.1M HCl (4 Hrs), pH 6.8 Phosphate buffer (4 Hrs) and pH 7.6 Phosphate buffer (4 Hrs).

(6) FIG. 6. Dissolution profile of Mesalamine in 0.1M HCl (2 Hrs), pH 6.0 Phosphate buffer (1 Hr) and pH 7.2 Phosphate buffer (3 Hrs).

DETAILED DESCRIPTION

(7) The present invention is related to a polymer based formulation for release of drugs and bio-actives at GIT specific sites. In one embodiment, the invention describes a dosage form comprising sodium alginate with bi- and/or trivalent chemically balanced cations to control the release of drug/bio-actives at specific time and at specific GIT sites. Herein, the applicant details a modified drug releasing pharmaceutical formulation as a capsule dosage form comprising Form-Fill-Seal (FFS) capsule processing. This brings ease of administration, subsequently avoiding inconvenient route of administration for dosage forms like suppositories and enemas. Avoidance of systemic absorption of drugs and consequently its unwanted distribution to tissues in the body is also achieved. This is applicable for site specific drug targeting for efficient local treatment of large bowel diseases, such as inflammatory bowel disease, ulcerative colitis, amebiasis, and colonic cancer. The polymeric capsule can deliver drugs or proteins and peptide drugs. Rectal administration is also limited by availability of lesser number of dosage forms (solutions, foams, enemas, and suppositories) and drug also remains localized to rectum and distal colon if administered by this route.

(8) In another embodiment, the invention describes the preparation of said formulation and its release profile for wide-ranging therapeutics as a “capsule” prepared by finely-tuned composition of bi- and/or trivalent cations and natural and/or synthetic polymer/s or combination thereof to control the release of drug/bioactives at specific time and at specific GIT sites.

(9) The term “modified release” includes, but is not limited to, immediate-, extended-, sustained-, lag- and pulsatile-, or delayed-, or combination of drug release profiles in pharmaceutical formulation.

(10) The present invention demonstrates a novel composition that offers greater multiplicity and flexibility in the release profile to be obtained with finely tuned natural polymer, sodium alginate using di- and/or tri-valent cations and natural/semi-synthetic/synthetic polymer. The relative ionic affinity and ability to form gels has been extensively studied for natural polymer, sodium alginate and a range of divalent cations is established the following series for the concentration of divalent cations required to bring about gelation of alginate: Ba<Pb<Cu<Sr<Cd<Ca<Zn<Ni<Co<Mn, Fe<Mg.

(11) The mechanical properties of alginate gels are dependent mainly upon and affinity towards bivalent or trivalent cations which bring about (a) stiffness of the individual polymer chains in alginate and (b) the nature and the strength of the forces whereby bi- or trivalent metal ions bind different chains together. Thus, alginate gels are crosslinked with bi- or trivalent cations.

(12) In the present invention, the release rate profiles of bioactives is achieved when the alginate concentration was varied from 1% to 6% w/v ionic concentrations. For example, when alginate concentration was higher than 2%, it promoted the saturation for ionic binding. Also, addition of Fe.sup.+++ promoted faster diffusion of Ca.sup.++ and reduced Ca.sup.++ equilibrium concentration. Also, Fe.sup.+++ ions entrapped in the alginate capsule promoted greater absorption of water compared to pure alginate gel.

(13) Further, by addition of Mg.sup.++ ions, the alginate achieves lower gelation almost 4 times than the equivalent amount of CaCl.sub.2 and/or FeCl.sub.3.

(14) The formulation of the present invention allows the release of drug/bioactive to reach at specific time and at specific site/s in a controlled manner e.g. extended-, sustained-, lag-, pulsatile-, or delayed-drug release profiles. The formulation is modulated by process of forming capsule shell to achieve desired release profile/s. Herein, the type and content of natural polymer blended and/or cross-linked with bi- and/or trivalent ions in the form of their salts with one or many natural or synthetic excipients/polymers to reach appropriate thickness of the layer on substrate was considered.

(15) It is observed that for oral administration of controlled-, sustained-, pulsatile-, extended- or delayed-release pharmaceutical compositions comprising bare API (No API processing), capsule shell composition provide a high unit dose of the active ingredient; exhibit desired in-vitro release profiles and in-vivo performance. Moreover, the formulation of the invention presents the advantage that it is cost effective since one polymer with bare API is needed to control the release of the active ingredient, thus facilitating relatively cheaper manufacturing process. In addition to optimum dissolution profile, the formulation of the invention presents an advantage of compatibility between natural polymer and drug/bioactive with better stability on storage.

(16) Capsule shell composition comprises sodium alginate, bi- and/ or trivalent cations in the form of their salts, for example: CaCl.sub.2, FeCl.sub.3, BaCl.sub.2, MgCl.sub.2, and MnCl.sub.2 and/ or polymers, for example: CMC, HPMC, HPC, starch, cross-linked sodium CMC/HPC; high-molecular weight polyvinylalcohols; gums such as natural gum, psyllium husk, tamarind gum, agar, agrose, sodium alginate, carrageenan, gum arabic, gum ghatti, gum karaya, gum tragacanth and xanthan gum; hydrophilic colloids such as alginates, carbopol and polyacrylamides; other substances such as arbinogalactan, pectin, amylopectin, gelatin, and N-vinyl lactams; polysaccharides; chitosan, hyaluronic acid and the like. Combinations of any two or more of these cations, and/or polymers having the required properties to achieve specific drug release profiles are within the scope of the invention.

(17) The dosage form of the present invention is a capsule comprising (a) drug/bioactives including peptide, proteins, natural/mineral oils, enzymes, vitamins and mixtures thereof; (b) polymer sodium alginate blended with natural or synthetic polymers. The polymer blends that can be used with cross-linked alginate includes but not limited to HPMC, CMC, PVA, gelatin, starch and so on.

(18) In one embodiment, the present invention comprises pharmaceutical composition of capsule shell comprising: (a) 0.01 to 6% w/v aqueous solution of Sodium alginate. (b) 0.025 to 18% w/v of bi- and/or trivalent ions in the form of their salts, (c) 0.01 to 10% w/v natural and/or semi-synthetic and/or synthetic polymer/s.

(19) In another embodiment, the pharmaceutical composition of the present invention comprise a therapeutically effective quantity of drug/bioactive or its pharmaceutically acceptable salts. The said composition is in a solid unit dosage form, as a capsule, made up of a single polymer of natural origin, which can be tuned to achieve various drug release profiles, such as, immediate (e.g. metformin capsule, FIG. 4), pulsatile (e.g. metoprolol hydrochloride capsule, FIG. 5) and colon targeted or delayed release (e.g. mesalamine capsule, FIG. 6).

(20) The pharmaceutical composition of the present invention provides protection from acidic environment in the stomach for proton pump inhibitor drugs without the need to apply enteric coating; these drugs include but not limited to Omeprazole, Rabeprazole, Pantoprazole and so on, which act by immediate drug release as soon as the dosage form reaches proximal part of small intestine. Thus the pharmaceutical composition of the present invention can deliver site specific drug release to colon for various APIs (e.g. mesalamine, budesonide, infliximab, etc.) as well as proteins and peptides, etc.

(21) The pharmaceutical composition of the present invention can also be prepared using any of the substrates such as stainless steel capsule pins, glass rods, teflon rods and brass capsule pins. It is envisaged that the pharmaceutical composition of the present invention which is a capsule formulation can be altered by achieving suitable thickness and toughness so as to deliver drug to the colonic region. The required thickness and toughness of the composition is achieved by increasing the number of capsule layers which may vary from one to eight. Thus the drug release can be modified or defined by the number of layers of the substrate. As the number of alginate layers increases, the release rate of bioactive from the capsule decreases.

(22) Furthermore, the pharmaceutical composition of the invention is delivered via systemic route when the drug/bioactive is a protein or a peptide.

(23) The pharmaceutical composition of the invention is useful for delivering the drug/bioactive at specific site and specific time in conditions such as IBD and cancer. Thus, the bioactive release rate can be tuned by changing the number of layers of capsules.

(24) Due to high ionic crosslinked system and H+ resistant alginate polymer capsule, the rate of hydration in stomach until its emptying time will be negligible. This will preserve the release of bioactive. Further, due to high ions the capsule will have lower hydration in intestinal buffers. The capsule at intestinal pH and due to long retention time there will initiate hydration resulting in swelling. While, it reaches to colon, the swelled capsule is expected to release the bioactive in colon pH. This can be tuned based on number of alginate layers and crosslinking ratio's of ions.

(25) Furthermore, the formulation of the invention delivers the bioactives by oral route when the drug/bioactive is protein or a peptide. It is expected that the capsule will protect these bioactives from early release in stomach and intestine. The rate of release will be delayed when the capsule reaches colon.

EXAMPLES

(26) The pharmaceutical composition of the present invention describes the dosage form comprising sodium alginate crosslinked with bi- and/or trivalent ions to control the release of drug/bio-actives at specific time and at specific GIT sites.

Example 1

(27) Suitable grade of alginate polymer was selected and a gel was prepared in distilled water in concentration ranging from 0.1-6% w/v. A substrate (e.g. stainless steel capsule pins, glass rods, teflon rods and brass capsule pins), was dipped into the alginate polymer gel for a time period of 10-60 seconds and removed. In the next stage, the substrate on which polymer gel was coated was dipped into aqueous solution of di- or trivalent ions or their mixtures (example, CaCl.sub.2, FeCl.sub.3 and MgCl.sub.2 having concentration from 0.025 to 12% w/v) thereof in the form of their salts and/or polymer having concentration from 0.05 to 6% w/v and 0.01 to 6% w/v respectively for a time period between 30 seconds to 1 hour (FIG. 1). This process allows cross-linking which leads to solidification of alginate. The substrate was then removed and dried in hot air oven at any temperature between 40° C. to 60° C. for time period of 1-4 hours.

(28) To get suitable thickness, layer by layer depositions from 1 to 8 layers of the polymer was achieved by repeating the same steps mentioned above (FIG. 1). Suitable thicknesses of the capsules allow generating different drug release profiles. Later on, the substrates containing dried polymer layers were again dipped into same concentration of salt/s as used in the initial stage of polymer cross-linking, which allows complete hydration and formed capsules were then removed with ease from the substrate.

Example 2

(29) Drugs or bio-actives are filled into alginate capsules prepared by method as mentioned in Example 1. The capsules were cross-linked with either polymeric blend/s or bi-/trivalent cations in the form of their salt/s and/or combinations thereof to achieve delivery. As the solubility of the drug changes the rate of release kinetics was altered. The cross-linking of cations with alginate showed varied release profiles ranging from immediate to delayed release up to 8 hours (FIG. 2). Therefore, cross-linked alginate capsules are prepared to obtain wide-ranging release profiles, to improve the bioavailability or stability and to target drug to specific sites. This also offers the advantages, like limiting drug fluctuation within therapeutic range, reducing the side effects, and decreasing dose frequency and improving patient compliance.

Example 3

(30) Capsules were allowed to dry and filled up with suitable API and subjected to in vitro drug/bio-active dissolution study. The characterization of final empty capsules was carried out by measuring the following physical specifications: Empty Capsule weight (mg) Empty Capsule weight of cap and body (mg) Empty Capsule-body volume capacity (ml) Empty Capsule weight capacity by formulation density (mg) Empty Capsule length (mm) Empty Capsule individual length/s of cap and body (mm) Empty Capsule external and internal diameter cap and body (mm)

Physical Characteristic of the Capsule is Provided in Table 1

(31) TABLE-US-00001 Physical characterization of final empty capsules Entry Parameter Size Range 1. Empty Capsule weight (mg) 170-180 2. Empty Capsule weight of cap (mg) 66-2  And Empty Capsule weight of body (mg) 102-112 3. Empty Capsule—body volume capacity (ml) 0.65-7   4. Empty Capsule weight capacity by 250-350 formulation density (mg) 5. Empty Capsule length (mm) 21.2-22.2 6. Empty Capsule individual length of cap 10.5-11.5 (mm) Empty Capsule individual length of body 18.2-19.2 (mm) 7. Empty Capsule external diameter of cap 7.4-7.8 (mm) Empty Capsule internal diameter of cap (mm) 7.2-7.6 Empty Capsule external diameter body (mm) 7.0-7.2 Empty Capsule internal diameter body (mm) 6.8-7.0

Example 4

(32) Dissolution profile of the following drug compounds were determined using alginate gel and its capsule and it was crosslinked with calcium chloride ions.

(33) In FIG. 3, dissolution profile of H.sup.+ proton pump inhibitor—Omeprazole as bare API was filled in alginate capsule. Omeprazole was protected from contact with acidic gastric acid in stomach until its relevance gastric empting time for more than 2 hours. This was achieved by designing>03 layered alginate capsules which are cross-linked with cations in the form of their salt such as Ca.sup.++.

(34) FIG. 4 shows the dissolution profile of Metformin hydrochloride in alginate capsule. 02 layers of alginate capsules were prepared and cross-linked with cations in the form of their salt/s such as Ca.sup.++. The dissolution profile indicated that ≥90% drug release happened within an hour for water-soluble drug was achieved. The said pharmaceutical composition is an immediate release dosage form, characterized by its dissolution profile wherein after 30 minutes at least 85% by weight of the active ingredient/s is dissolved.

(35) FIG. 5 shows the dissolution profile for alginate capsule having Metoprolol tartrate in 0.1M HCl (4 Hrs), pH 6.8 Phosphate buffer (4 Hrs.) and pH 6.8 phosphate buffer (4 Hrs). The results indicate that a pulsatile release with chronopharmacological behavior. This was achieved by 03 layers of alginate which was cross-linked with bivalent cations in the form of their salt/s such as Ca.sup.++. The pulsatile release of Metoprolol tartrate with an hour of lag period influence drug release that ideally matches the circadian rhythm (24 hour) of the body in association with a specific disease.

(36) FIG. 6 shows dissolution profile for alginate capsule having Mesalamine in 0.1M HCl (2 Hrs), pH 6.0 phosphate buffer (1 Hr) and pH 7.2 Phosphate buffer (3 hrs). The results indicate colon targeted modified release. This was achieved by 03 layers of alginate cross-linked with bivalent cations in the form of their salt/s such as Ca.sup.++. The delayed release of Mesalamine with 0≥3 hour of lag period influence drug to reach preferred sites of delivery-distal gut (ileum and/or colon) without absorption from the small intestine ability at distal sites in the gut and its release in colon that increases the residence time to treat Ulcerative colitis and IBD. With altering the number of the alginate capsule, modified-profiles releases were achieved from immediate-release viz. metformin hydrochloride to a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release [ER, XR, XL] dosage) or to a specific GIT target viz. colon (targeted-release dosage).