FIELD OF THE INVENTION
The present invention relates to improvised pharmaceutical compositions permitting ingestion via oral delivery of proteins/peptides or their conjugates, and/or cation-insulin conjugate complexes demonstrating desirable pharmacokinetic profiles and potency in efficacy models of diabetes in dogs and humans. A preferred formulation comprises 0.01% - 20% w/w of insulin, insulin compound conjugates and/or cation insulin conjugates, 10% - 60% w/w of one or more fatty acid components selected from saturated or unsaturated C4-C12 fatty acids and/or salts of such fatty acids and additionally contains optimal amounts of other pharmaceutically suitable polymer excipients which permit improved solubility, dissolution rate and effective bioavailability of poorly water soluble compositions and consistent in-vivo release profiles upon scalability during manufacture . A further aspect of the invention features the process of preparing the aforesaid formulations.
BACKGROUND AND PRIOR ART OF THE INVENTION
Conventional subcutaneous routes of insulin administration are increasingly being researched to be replaced by oral drug delivery mechanisms that would not alter their physiological clinical activity. Problems confronted in this field of art in designing an effective oral drug delivery system for biological macromolecules has been mainly attributed to its susceptibility to enzymatic degradation and low epithelial permeability. Further, the structure and conformation of insulin are easily altered when exposed to formulation and process conditions leading to a loss of biological activity. Some of the approaches to combat these limitations involved the use of insulin analogs, administration of peptides such as amylin, glucagon-like peptide, C-peptides, inhaled forms, intranasal forms which have not satisfactorily addressed the limitations of bioavailability individually.
There is a need in the art for pharmaceutically acceptable complexes including derivatized insulin conjugates having increased bioavailability or other improved pharmaceutical attributes relative to the existing conjugates. Furthermore these improved conjugates need to delivered in the form of a stable and improvised formulation that easily maximizes the benefits of oral delivery of proteins. The instant invention applies a combined approach of an improved insulin conjugate with

increased bioavailability and an improved formulation to address the limitations of insulin delivery.
Examples of insulin compounds include human insulin, lyspro insulin, des30 insulin, native proinsulin, artificial proinsulins, etc. The cation component may, for example, be a divalent metal cation selected from the group consisting of Zn-H-, Mn++, Ca++, Fe++, Ni-H-, Cu+H-, Co-H- and MgH-+. The cation-insulin compound conjugate complexes also include a modifying moiety coupled (eg., covalently or ionically) to the insulin compound to provide an insulin compound conjugate. Further, the modifying moiety is selected to render the insulin compound conjugate equally or more soluble than a corresponding unconjugated insulin compound, and the water solubility of the insulin compound conjugate is decreased by the addition of zinc. The modifying moiety is selected to render the insulin compound conjugate equally or more soluble than a corresponding unconjugated insulin compound; the water solubility of the insulin compound conjugate is decreased by the addition of zinc; and water solubility of the complex is greater than the water solubility of insulin compound.
Examples of suitable modifying moieties and insulin conjugates useful in the preparation of compositions can be found in US patent Nos 7,060675, 6,303,569, 6,214,330, 6,113906, 5,985,263, 5,900,402, 5,681,811, 5,637,749, 5,612,640, 5,567,422, 5,405,877, 5,359,030 the entire disclosures of which are incorporated herein by reference. Additional examples of such cation-insulin compound conjugate complexes are provided in US patent applications US2003/083232, US 2006/0019873 and US2006/0019874.
WOOO/50012 discloses solid oral dosage forms comprising a drug and an enhancer, wherein the enhancer is a salt of a medium chain fatty acid with a carbon chain length of about 6-20 carbon atoms. US2006/0018874 cover a solid pharmaceutical composition formulated for oral administration by ingestion, having 0.1 to 75% w/w fatty acid component, where the fatty acid component comprises saturated or unsaturated fatty acids and/or salts and a therapeutic agent.
Notwithstanding the foregoing, there still exists a need for manufacture of viable oral insulin formulations that can overcome problems associated with loss of biological activity during manufacture and at the same time exhibit enhanced resistance to enzymatic degradation in-vivo post ingestion. The present invention addresses both

requirements. Thereby, the invention addresses the problems confronted in the art to design a highly effective oral insulin-conjugate drug delivery mechanism. The invention exhibits various advantages with respect to the dosing and convenient method of administration. The invention constitutes yet another advantage over the prior art compositions as the inventors propose that the claimed rationally designed oral formulation of IN-105 with measured components of other excipients and the process of manufacturing the orally administrable tablets are easily scalable. Further, attributed to this rationally designed oral formulation and the process of making the same, the scalability factor does not impact the in-vivo drug performance or its in-vivo release profile. Other objects and advantages of the present invention will be more fully apparent to those of ordinary skill in art, in light of the ensuing disclosure and appended claims.
OBJECTIVES OF THE INVENTION
The principal object of the present invention is to provide an orally administrable
solid pharmaceutical composition of insulin.
Another object of the present invention is to provide a process for the preparation of
orally administrable solid pharmaceutical composition of insulin.
Yet another object of the present invention is to provide different dosage
compositions of orally administrable solid pharmaceutical composition of insulin.
Still another object of the present invention is to have a control over the blood glucose
levels in diabetic patients.
STATEMENT OF THE INVENTION
Accordingly, the present invention provides an orally administrable solid pharmaceutical composition, said composition comprising cation-insulin conjugate complex with saturated or unsaturated C4 - C12 fatty acids, fatty acid esters or salts thereof and at least three pharmaceutically acceptable excipients selected from a group comprising binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and solubilizers; a process for manufacturing an orally administrable solid pharmaceutical composition of a cation-insulin conjugate complex comprising saturated or unsaturated C4 - C12 fatty acids or salts thereof and at least three pharmaceutically acceptable excipients selected from the group comprising binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and solubilizers;

and a 5-500 mg tablet composition of an cation-insulin conjugate complex comprising saturated or unsaturated C4 - C12 fatty acids, fatty acid esters, or salts thereof and at least three pharmaceutically acceptable excipients selected from the group comprising binders, disintegrants, lubricants, plasticizers and permeation enhancers.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
FIG 1: Mean plasma insulin profile - IN-105 formulation tablets (FDT-3)
FIG 2: Normalized glucose profile in administration of FDT-3
FIG 3: Mean plasma insulin profile - FN-105 formulation tablets (FDT-19)
FIG 4: Normalized glucose profile in administration of FDT-19
FIG 5: Mean plasma insulin profile - IN-105 formulation tablets (FDT-20)
FIG 6; Glucose profile after administration of FDT-20
DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWINGS
The present invention is in relation to an orally administrable solid pharmaceutical
composition, said composition comprising cation-insulin conjugate complex with
saturated or unsaturated C4 - C12 fatty acids, fatty acid esters or salts thereof and at
least three pharmaceutically acceptable excipients selected from a group comprising
binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and
solubilizers.
In another embodiment of the present invention, wherein the cation-insulin conjugate
complex is IN-105.
In yet another embodiment of the present invention, wherein the fatty acid
components are selected from a group comprising capric acid, lauric acid optionally
from a source of sodium caprate and sodium laurate and any salts thereof.
In still another embodiment of the present invention, wherein said binders are selected
from a group comprising polyvinylpyrrolidone, carboxymethylcellulose,
methylcellulose, starch, gelatin, sugars, natural and synthetic gums and combinations
thereof.
In still another embodiment of the present invention, wherein said diluents are
selected from a group comprising calcium salts, cellulose or cellulose derivatives,
palatinose, organic acids, sugar and sugar alcohols, pectate salts and combinations
thereof.

In still another embodiment of the present invention, wherein said disintegrants are
selected from the group comprising cross-linked polyvinylpyrrolidone,
carboxymethylcellulose, methyl cellulose, cation-exchange resins, alginic acid, guar
gum and combinations thereof
In still another embodiment of the present invention, wherein said lubricants are
selected from a group comprising magnesium stearate, sodium stearate, sodium
benzoate, sodium acetate, fumaric acid, polyethylene glycols, alanine and glycine.
In still another embodiment of the present invention, wherein said permeation
enhancers are selected from a group comprising sodium lauryl sulfate, sodium laurate,
palmitoyl carnitine, phosphatidylcholine, cyclodextrin and derivatives thereof,
camithine and their derivatives, mucoadhesive polymers, zonula occludins toxin, bile
salts, fatty acids or combinations thereof
In still another embodiment of the present invention, wherein said plasticizers are
selected from a group comprising polyethylene glycol, propylene glycol, acetyl
citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil,
acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate,
dibutylsuccinate, dibutyl phthalate, dioctylphthalate, dibutylsebacate, triethylcitrate,
tributylcitrate, glyceroltributyrate, glyceryl triacetate, and combinations thereof
In still another embodiment of the present invention, wherein the oral dosage form is
in the form of a tablet, capsule, particles, powder or sachet and dry suspensions.
In still another embodiment of the present invention, wherein the excipients are
preferably polyvinylpyrrolidone as binder, mannitol as diluent, magnesium stearate as
lubricant, sodium lauryl sulphate and beta-cyclodextrin as permeation enhancer and
polyethylene glycol as plasticizer.
In still another embodiment of the present invention, wherein the dose to achieve a
maximum control of post prandial blood glucose concentration in diabetic patients
within 5-60 minutes post - administration.
In still another embodiment of the present invention, wherein said composition
produces lowered serum glucose in human patients by at least 5% with in 120 minutes
post oral administration.
The present invention is in relation to a process for manufacturing an orally
administrable solid pharmaceutical composition of a cation-insulin conjugate complex
comprising saturated or unsaturated C4 - C12 fatty acids or salts thereof and at least
three pharmaceutically acceptable excipients selected from the group comprising

binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and
solubilizers.
In another embodiment of the present invention, wherein said process comprising
steps of:
a) grinding a suitable saturated or unsaturated C4-C12 fatty acids and/or salts of such fatty acid;
b) granulating the resulting fatty acid obtained from step (a) with an organic solvent;
c) air-drying the granules obtained from step (b);
d) rasping the dried granules through a mesh to obtain granules of desired particle size; and
e) blending the fatty acid granules with the cation-insulin conjugate complex with the other excipients to obtain the composition.
In still another embodiment of the present invention, wherein said process comprising steps of:
a) grinding suitable saturated or unsaturated C4-C12 fatty acids and/or salts of such fatty acid and a binder;
b) suspending the cation-insulin conjugate complex in an organic solvent using the binder to form a wet mass;
c) granulation of the components obtained from step (b) using the binder;
d) rasping the dried granules of step (c); and
e) blending the granules with other excipients to obtain the composition.
In still another embodiment of the present invention, wherein the blended mixture is
compressed to obtain solid dosage form, preferably tablet form.
In still another embodiment of the present invention, wherein said organic solvent is selected from a group comprising isopropanol, acetone, methyl alcohol, methyl isobutyl ketone, chloroform, 1-propanol, 2-propanol, acetonitrile, 1-butanol, 2-butanol, ethyl alcohol, cyclohexane, dioxane, ethyl acetate, dimethylformamide, dichloroethane, hexane, isooctane, methylene chloride, tert-butyl alchohol, toluene, carbon tetrachloride, or combinations thereof
The present invention is in relation to a 5-500 mg tablet composition of an cation-insulin conjugate complex comprising saturated or unsaturated C4 - C12 fatty acids, fatty acid esters, or salts thereof and at least three pharmaceutically acceptable

excipients selected from the group comprising binders, disintegrants, lubricants, plasticizers and permeation enhancers.
In another embodiment of the present invention, wherein the preferable dosage ranges are selected from a group comprising 50 mg, 100 mg, 150mg, 200mg and 250mg tablet compositions.
The invention further provides a method of treatment of diabetes, impaired glucose
tolerance, early stage diabetes, and late stage diabetes in animals, preferably humans,
and a method of achieving glucose homeostasis, comprising administering one or
more unit doses of the dosage forms an immediate release formulation comprising
proteins/peptides, their conjugates, and/or cation-polypeptide conjugate complexes
with suitable excipients that enhance resistance of the therapeutically active agent to
degradation.
DEFINITIONS:
In describing and claiming the present invention, the following terminology will be
used in accordance with the definitions set out herein.
The "cation-insulin compound conjugate" includes any insulin compound
component. The insulin compound may, for example, be a mammalian insulin
compound, such as human insulin, or an insulin compound derivatives or analogs.
The therapeutic agent specifically relates to the molecule IN-105. IN-105 is an insulin
molecule conjugated at the epsilon amino acid Lysine at position B29 of the insulin
B-Chain with an ampiphilic oligomer of structural formula CH3O-(C4H2O)3-CH2-CH2-
COOH.The molecule may be monoconjugated at Al, Bl and B29, di-conjugated at
various combinations of Al, Bl and B29, or triconjugated at various combinations of
Al,Bl and B29.
"Therapeutically effective amount" refers to an amount of insulin included in the
dosage forms of the invention which is sufficient to achieve a clinically relevant
control of blood glucose concentrations in a human diabetic patient either in the
fasting state or in the fed state effective, during the dosing interval.
As used herein, "diluents"/'Tillers"/"bulking agents" are inert substances added to
increase the bulk of the formulation to make the tablet a practical size for
compression. Commonly used diluents in contemplated for use in the present
invention include sugar alcohols, organic acids, galen IQ, palatinose, cellulose and

cellulose derivatives, calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, silica, and the like. As used herein, "binders" are agents used to impart cohesive qualities to the powdered material. Binders, or "granulators" as they are sometimes known, impart cohesiveness to the tablet formulation, which insures the tablet remaining intact after compression, as well as improving the free-flowing qualities by the formulation of granules of desired hardness and size. Materials commonly used as binders include carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, starch; gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, Veegum, microcrystalline cellulose, microcrystalline dextrose, amylose, and larch arabogalactan, and the like. Polyvinylpyrolidone is used in context of the present invention.
As used herein, "disintegrators" or "disintegrants" are substances that facilitate the breakup or facilitate disintegration of tablets after administration. Materials serving as disintegrants have been chemically classified as starches, clays, celluloses, algins, or gums. Other disintegrators include Veegum HV, methylcellulose, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, cross-linked lyvinpoylpyrrolidone, carboxymethylcellulose, and the like.
"Lubricant" may be selected from the group comprising magnesium stearate, sodium steareate, sodium benzoate, sodium acetate, fumaric acid, polyethylenglycols (PEG) higher than 4000, alanine and glycine. Preferred lubricant in context of the present invention is magnesium stearate or sodium stearate.
"Magnesium stearate" means a compound of magnesium with a mixture of solid organic acids obtained from fats, and chiefly consists of variable proportions of magnesium stearate and magnesium palmitate. It is used as a pharmaceutical necessity (lubricant) in the manufacture of compressed tablets.
"Permeation enhancers" means any compound that increases membrane permeability and facilitate drug transport through the biological membrane, thereby improving the bioavailability of the delivered therapeutic agent. Suitable membrane-permeation enhancers include surfactants such as sodium lauryl sulfate, sodium laurate, palmitoyl carnitine, Laureth-9, phosphatidylcholine, cyclodextrin and derivatives thereof, bile salts such as sodium glycochlate, sodium deoxycholate,

sodium taurocholate, and sodium fusidate, chelating agents including EDTA, citric acid and salicylates, and fatty acids (e.g., oleic acid, lauric acid, acylcamitines, mono-and diglycerides), L-camithine and derivatives, muco-adhesive polymers, ZOT (zonula occludans toxin) or combinations thereof.
"Plasticizers" which are selected from the group consisting of acetyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, dibutyl phthalate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, glyceryl triacetate, polyethyleneglycol, propylene glycol, and mixtures thereof. The plasticizer is most preferably polyethylene glycol. The plasticizer may be present upto 40% w/w of the film forming polymer. Representative plasticizer used in context of the present invention is PEG (polyethylene glycol) "Polyalkylene glycol" or "PAG" refers to substituted or unsubstituted, linear or branched polyalkylene glycol polymers such as polyethylene glycol (PEG), polypropylene glycol (PPG), and polybutylene glycol (PBG), and combinations thereof (e.g., linear or branched polymers including combinations of two or more different PAG subunits, such as two or more different PAG units selected from PEG, PPG, PPG, and PBG subunits), and includes the monoalkylether of the polyalkylene glycol. The term PAG subunit means a single PAG unit, e.g., "PEG subunit" refers to a single polyethylene glycol unit, e.g., -(CH2CH2O.)-, "PPG subunit" refers to a single polypropylene glycol unit, e.g., -(CH2CH2CH2O)-, and "PBG subunit" refers to a single polypropylene glycol unit, e.g., -(CH2CH2CH2CH2O)-. PAGs and/or PAG subunits also include substituted PAGs or PAG subunits, e.g., PAGs including alkyl side chains, such as methyl, ethyl or propyl side chains, or carbonyl side chains, as well as PAGs including one or more branched PAG subunits, such as iso-PPG or iso-PBG.
"Solubilizers" may be any substance that enhances the aqueous solubility of a drug. As used herein, ''pharmaceutically acceptable carrier" comprises one or several agents selected from the group consisting of carbohydrates and modified carbohydrates and derivatives thereof, polyethylene and/or polypropylene glycol and derivatives thereof, inorganic fillers or lubricating agents, fatty acids and their esters and salts, preservatives and coating agents.
As referred in the specification "effective amount" means an amount of any agent that is nontoxic but sufficient to provide the desired local or systemic effect and

performance at a reasonable benefit/risk ratio attending any medical treatment. For example, an effective amount of a lubricant is an amount sufficient to function for lubricating the composition for tableting purposes without providing any detrimental effects.
In context of the present invention "organic solvents" refers to any solvent of nonaqueous origin, including liquid polymers and mixtures thereof. Organic solvents suitable for the present invention include: acetone, methyl alcohol, methyl isobutyl ketone, chloroform, 1-propanol, isopropanol, 2-propanol, acetonitrile, 1-butanol, 2-butanol, ethyl alcohol, cyclohexane, dioxane, ethyl acetate, dimethylformamide, dichloroethane, hexane, isooctane, methylene chloride, tert-butyl alchohol, toluene, carbon tetrachloride, or combinations thereof
The primary object of the invention is to provide an immediate release formulation comprising proteins/peptides, their conjugates, and/or cation-polypeptide conjugate complexes demonstrating desirable pharmacokinetic profiles and potency in efficacy models of diabetes in humans upon oral delivery. The current state of the art recognizes the instability of unmodified insulin in the gastrointestinal tract and has endeavored to circumvent these problems by developing a rationally designed formulation for immediate release.
A preferred embodiment of the present invention relates to orally deliverable formulation comprising 0.01% - 20% w/w of insulin, insulin compound conjugates and/or cation insulin conjugates, 10% - 60% w/w of one or more fatty acid components selected from saturated or unsaturated C4-C12 fatty acids and/or salts of such fatty acids, 10% - 60% w/w of a diluent, 1% - 20% of disintegrants, 0.01% - 5% of binder and 0.01% - 5% of adsorbent including but not limited to other suitable pharmaceutically acceptable carriers.
Accordingly, one aspect the invention relates to a formulation comprising at least one biologically active compound selected from derivatized insulin conjugates, insulin analogues, insulin complexes including but not limited to other therapeutic agents with insulin-like activity.
In yet another aspect, the invention provides a process of manufacturing the above mentioned orally deliverable formulations under optimal operational conditions with suitable excipients that enhance resistance of the therapeutically active agent to degradation.

In yet another preferred aspect, the process of manufacture of the orally deliverable tablet comprising at least one biologically active compound selected from proteins/peptides, their conjugates, and/or cation-polypeptide conjugate complexes possessing resistance to enzymatic degradation comprising the steps:
1. Grinding a suitable saturated or unsaturated C4-C12 fatty acid and/or salts of such a fatty acid.
2. Granulating the resulting fatty acid obtained from step (1) with an organic solvent.
3. Air-drying the granules obtained from step (2).
4. Rasping the dried granules through a mesh to obtain granules of desired size of about 250µm.
5. Blending the fatty acid granules, cation-insulin compound conjugate with other excipients.
6. Compressing the blended mixture for tablet formation.
In accordance with the above objects and others, the invention is directed in part to an oral solid dosage form comprising a dose of modified insulin which achieves a maximum control of post prandial blood glucose concentration in diabetic patients within 20-30 minutes post - administration.
Those of skill will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound. The dosage unit form may be a liquid or a solid, such as a tablet, capsule or particles, including a powder or sachet. Other objects and advantages of the present invention will be more fully apparent to those of ordinary skill in art, in light of the ensuing disclosure and appended claims.
The invention contemplates use of coating agents which may include both nonfunctional (insta-coat, kollicoat IR) or enteric coating agents such as cellulose based polymers, film coating agents or polymethyl acrylate and other coating agents known to a person of ordinary skill in the art.
The present invention relates in one broad compositional aspect to formulations including covalently conjugated therapeutic agent complexes wherein the therapeutic agent is covalently bonded to one or more molecules of a polymer incorporating as an

integral part of said polymer a hydrophilic moiety, e.g., a polyalkylene glycol moiety, and a lipophilic moiety, e.g., a fatty acid moiety. In one preferred aspect, the therapeutic agent may be covalently conjugated by covalent bonding with one or more molecules of a linear polyalkylene glycol polymer incorporated in which, as an integral part thereof is a lipophilic moiety, e.g., a fatty acid moiety. The modified insulin conjugates as used in the present invention are developed by attaching low-molecular-weight polymers or oligomers that are ampiphilic in nature comprising a polyethylene glycol portion which is hydrophilic while the alkyl chain is lipophilic. The attachment modifies the solubility of the drug molecule and stabilizes the protein or peptide from enzymatic degradation in the gastrointestinal tract. The conjugated drug is absorbed more efficiently across the GI wall than the drug in its native state. On traversing to the blood stream the bond between the hydrophilic and hydrophobic chain is hydrolyzed leaving the highly active insulin-PEG compound circulating in the blood thus favorably altering the pharmacokinetics of the drug. The present invention specifically relates to the molecule IN-105. IN-105 is an insulin molecule conjugated at the epsilon amino acid Lysine at position B29 of the insulin B-chain with an ampiphilic oligomer of structural formula CH3O-(C4H2O)3-CH2"CH2-COOH.
The rationally formulated composition is bioavailable upon immediate release. In associatively conjugated therapeutic agent of the above-described type, the polymer component may be suitably constructed, modified, or appropriately functionalized to impart the ability for associative conjugation in a selective manner. In one aspect, the invention provides fatty acid compositions with one or more saturated or unsaturated C4, C5, C6, C7, C8, C9 or C01 fatty acids and/or sahs of such fatty acids. Preferred fatty acids are caprylic, capric, myristic and lauric. Preferred fatty acid sahs are sodium sahs of caprylic, capric, myristic and lauric acid. The modifying moieties may include other hydrophilic polymers. Examples include poly(oxyethylated polyols) such as poly(oxyethylated glycerol), poly(oxyethylated sorbitol), and poly(oxyethylated glucose); poly(vinyl alcohol) ("PVA"); dextran; carbohydrate-based polymers and the like. The polymers can be homopolymers or random or block copolymers and terpolymers based on the monomers of the above polymers, linear chain or branched.
The total amount of cation-insulin compound conjugate to be used can be determined by those skilled in the art. The amount of therapuetic agent is an amount effective to

accomplish the purpose of the particular active agent. The amount in the composition is a therapeutically effective dose, i.e., a pharmacologically or biologically effective amount. However, the amount can be less than a pharmacologically or biologically effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, because the dosage unit form may contain a multiplicity of delivery agent/biologically or chemically active agent compositions or may contain a divided pharmacologically or biologically effective amount. The total effective amounts can then be administered in cumulative units containing, in total, pharmacologically or biologically or chemically active amounts of biologically or pharmacologically active agent.
In certain preferred embodiments, the pharmaceutical composition contained in one or more dosage forms comprises from about 5 mg to about 800 mg of delivery agent, preferably about 10 mg to about 600 mg, more preferably from about 10 mg to about 400 mg, even more preferably from about 25 mg to about 200 mg, most preferably about 75 mg, 100 mg or 150 mg. More preferably, the composition provides a peak plasma insulin concentration within about 15 minutes to about 60 minutes after oral administration and more preferably within about 10-20 minutes after oral administration to fed diabetic patients.
It is contemplated for purposes of the present invention that dosage forms of the present invenfion comprising therapeutically effective amounts of insulin may include one or more unit doses (e.g., tablets, capsules, powders, semisolids, oral sprays, sublingual tablets (e.g. gelcaps or films) to achieve the therapeutic effect. It is ftirther contemplated for the purposes of the present invention that a preferred embodiment of the dosage form is an oral dosage form.
In some cases, the complexed insulin compound conjugate will exhibit an extended or otherwise altered pK profile relative to a scientifically acceptable control, such as a corresponding uncomplexed insulin compound conjugate. pK profile can be assessed using standard in vivo experiments, e.g., in mice, rats, dogs, or humans. Assays described herein for assessing the attributes of cation-insulin compound conjugate complexes are an aspect of the invention.
In a preferred aspect, the process of manufacture of the orally deliverable tablet comprising atleast one biologically active compound selected from proteins/peptides.

their conjugates, and/or cation-polypeptide conjugate complexes possessing resistance to enzymatic degradation comprising the steps:
1. Grinding a suitable saturated or unsaturated C4-C12 fatty acid and/or salts of such a fatty acid.
2. Granulating the resulting fatty acid obtained from step (1) with an organic solvent.
3. Air-drying the granules obtained from step (2).
4. Rasping the dried granules through a mesh to obtain granules of desired particle size
5. Blending the fatty acid granules with the cation-insulin compound conjugate, disintegrant, binder and other excipients.
6. Tablet compression, polishing and packing
In yet another preferred aspect, the process of manufacture of the orally deliverable tablet comprising at least one biologically active compound selected from proteins/peptides, their conjugates, and/or cation-polypeptide conjugate complexes possessing resistance to enzymatic degradation comprising the steps:
1. Grinding suitable saturated or unsaturated C4-C12 fatty acid and/or salts of such a fatty acid such as sodium caprate, PVP-K-30.
2. Suspending IN-105 in an organic solvent using PVPK-30 as a binder to form a wet mass
3. Granulation of the resulting components using PVP-K30 as a binder
4. Rasping of dried Sodium caprate granules through 45# (355(im)
5. Blending of sodium caprate granules with other excipients.
6. Tablet compression, polishing and packing.
Accordingly, as per various embodiments of the invention exhibits various advantages with respect to the dosing and convenient method of administration. The invention constitutes yet another advantage over the prior art compositions as the inventors propose that the claimed rationally designed oral formulation of IN-105 with measured components of other excipients and the process of manufacturing the orally administrable tablets are easily scalable without affecting the release profile in-vitro or in-vivo. Further, attributed to this rationally designed oral formulation and the process of making the same, the scalability factor does not impact the in-vivo drug performance or its in-vivo release profile. The invention will be better understood

from the following Examples. However, those of ordinary skill in the art will readily understand that these Examples are merely illustrative of the invention that is defined in the claims that follow thereafter.
The technology of the instant Application is further elaborated with the help of following examples. However, the examples should not be construed to limit the scope of the invention. The following Examples represent preferred embodiments of the present invention. EXAMPLE I:
Drug formulations in accordance with the present invention were prepared and tested. Accordingly, required amount of ground Sodium caprate was weighed accurately in to a planetary mixture and then granulate with 700ml of isopropyl alcohol. The amount of isopropyl alcohol added to convert the powder mixture to granular form was calculated. The wet mass was scraped every 5 minutes, such that the mixture does not stick to the wall of the planetary mixture. The wet mass was passed through 18# sieve in a wet granulator and air dried overnight under the hood.
Moisture Content of Granules: Sample Weight = 0.662 gm; % of moisture content =2.27 %
Appropriate quantity of IN-105, sodium caprate granules, KoUidon CL and pearlitol was weighed and passed through a 60# sieve and mixed in a double cone blender for 20 minutes at a speed of 12 r.p.m. After homogenous mixing for 20 minutes, the blend was lubricated with aerosol and magnesium stearate for 3 minutes at a speed of 88-90 r.p.m. TABLE: I


The tablets prepared as per the example I, were tested in 26 hrs fasted six healthy male beagle dogs. Each tablet was administered with 20 ml of water. The blood samples were collected for measuring blood glucose and plasma insulin levels. As represented in FIG.l and FIG.2 the tablet resulted in a rapid increase of plasma insulin levels showing a Cmax of about 100mU/ml with a Tmax of 20 minutes from the time of administration resulting in a corresponding drop of about 35% in plasma glucose concentration.
EXAMPLE 2:
Milled sodium caprate was accurately weighed and taken in a planetary mixer and mixed for 2 minutes. Required quantities of IN-105 weighed was added to isopropanol with 0.35% w/w of polyvinylpyrrolidone to form a suspension and stirred well for 30 minutes using a magnetic stirrer. An appropriate amount of isopropanol was added during granulation. The granules were mixed for 15 min in planetary mixer and passed through 14# sieve a dried in Hot Air Oven for 2 hrs at 30^C.

Speed of Planetary mixer = 4 for 15 min. Volume of IPA added = 200ml. 0.7gm (0.35%) PVP + 7.33GM. IN-105 was suspended in 80 ml of IPA. Remaining 6.3gm of PVP was suspended in 40 ml of IPA. Remaining amount of IPA was added to form a hard wet mass.
BLENDING PROCESS:
Accurately weighed quantity of IN-105 + Sodium caprate + PVP K-30 granules, Pearlitol and Kollidon CL were passed through 45# sieve and mixed in a octagonal blender. After homogenous mixing the blend was lubricated with Aerosil and Magnesium stearate, mixed well and compressed into tablets.


Tablets prepared as per the example 2, were tested in 26 hours fasted six healthy male beagle dogs. Each tablet was administered with 20 ml of water. The blood samples were collected for measuring blood glucose and plasma insulin levels. As represented in FIG.3 and FIG.4, the tablets resulted in an rapid increase in plasma insulin levels showing a Cmax of about 75mU/ml with a Tmax of 20 minutes from the time of administration. This resulted in a corresponding drop of about 35% in plasma glucose concentration from the baseline. EXAMPLES:
Accurately weighed Qty of IN-105, Sodium caprate + Beta-Cyclodextrin complex, Sodium bicarbonate and KoUidon CL were passed through 45# sieve and mixed in a Polyethylene bag. After homogenous mixing the blend was lubricated with Aerosil and Magnesium stearate, mixed well and compressed into tablets. TABLE 4:


EXAMPLE 4:
Accurately weighed Qty of IN-105, Sodium Lauryl sulphate, Kollidon CL and Pearlitol were passed through 45# sieve and mixed in a octagonal blender.After homogenous mixing, the blend was lubricated with Aerosil and Magnesium stearate, mixed well and compressed in to Tablets.

Tablets prepared as described in example 4, were tested in 26 hrs fasted six healthy male beagle dogs. Each tablet was administered with 20 ml of water. The blood samples were collected for measuring blood glucose and plasma insulin levels. Results obtained is represented in FIG. 5 and FIG. 6 EXAMPLE 5:
PREPARATION OF SODIUM CAPRATE, SODIUM BICARBONATE AND PEARLITOL GRANULES WITH PVP K-30 (2%WAV) AS BINDER AND PEG 6000 (1% WAV) AS PLASTICIZER AND IN-105 ADDED DURING GRANULATION.
Accurately weighed quantity of Ground Sodium caprate, Sodium bicarbonate and Pearlitol was taken in planetary mixer, dry mixing was done for 5 min. Meanwhile PVP K 30 was dissolved in IPA and IN-105 was suspended. PEG 6000 was dissolved in water (5% v/v). The Solution were stirred well using Magnetic Stirrer. Sodium caprate, Sodium bicarbonate and Pearlitol were granulated using PVPK and PEG solution as granulating agent. The process was carried out for 20 min. The Wet mass formed was passed through 18# sieve in Wet granulator and dried in LAP.

volume ot IPA added - 130 ml.
100 ml = IN-105 + PVP k. 6 ml = PEG in water. Speed of Planetary mixer = 2-4 for
20 min. Speed of Wet granulator - 200 rpm.
Moisture content of granules.
Weight of Sample - 0.525 gm.
% Moisture content - 1.99 %.
TABLE 6:

Accurately weighed quantity of IN-105 + Sodium caprate + Sodium bicarbonate + Pearlitol + PVP K 30 and PEG granules were passed through 35# seive and mixed with Kollidon CL in a doubl cone blender. After homogenous mixing the blend was lubricated with Aerosil and Magnesium stearate, mixed well and compressed into tablets.
These are preferred dose proportional formulations giving desirable drug release profiles. These formulations provide an approximately consistent release of IN-105 have been envisioned.

The above description and examples have been given for ease of understanding only. No unnecessary limitations should be understood there from, as modifications will be obvious to those skilled in the art who will recognize that the invention can be practiced with modifications and variations within the spirit of the appended claims.

WE CLAIM:
1. An orally administrable solid pharmaceutical composition, said composition comprising cation-insulin conjugate complex with saturated or unsaturated C4 - C12 fatty acids, fatty acid esters or salts thereof and at least three pharmaceutically acceptable excipients selected from a group comprising binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and solubilizers.
2. The pharmaceutical composition as claimed in claim 1, wherein the cation-insulin conjugate complex is IN-105.
3. The pharmaceutical composition as claimed in claim 1, wherein the fatty acid components are selected from a group comprising capric acid, lauric acid optionally from a source of sodium caprate and sodium laurate and any salts thereof.
4. The pharmaceutical composition as claimed in claim 1, wherein said binders are selected from a group comprising polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, starch, gelatin, sugars, natural and synthetic gums and combinations thereof.
5. The pharmaceutical composition as claimed in claim 1, wherein said diluents are selected from a group comprising calcium salts, cellulose or cellulose derivatives, palatinose, organic acids, sugar and sugar alcohols, pectate salts and combinations thereof.
6. The pharmaceutical composition as claimed in claim 1, wherein said disintegrants are selected from the group comprising cross-linked polyvinylpyrrolidone, carboxymethylcellulose, methyl cellulose, cation-exchange resins, alginic acid, guar gum and combinations thereof.
7. The pharmaceutical composition as claimed in claim 1, wherein said lubricants are selected from a group comprising magnesium stearate, sodium stearate, sodium benzoate, sodium acetate, fumaric acid, polyethylene glycols, alanine and glycine.
8. The pharmaceutical composition as claimed in claim 1, wherein said permeation enhancers are selected from a group comprising sodium lauryl sulfate, sodium laurate, palmitoyl carnitine, phosphatidylcholine, cyclodextrin and derivatives thereof, carnithine and their derivatives, mucoadhesive

polymers, zonula occludins toxin, bile salts, fatty acids or combinations thereof.
9. The pharmaceutical composition as claimed in claim 1, wherein said plasticizers are selected from a group comprising polyethylene glycol, propylene glycol, acetyl citrate, triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyltriethyl citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethyl fumarate, dibutylsuccinate, dibutyl phthalate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, glyceryl triacetate, and combinations thereof.
10. The pharmaceutical composition as claimed in claim 1, wherein the oral dosage form is in the form of a tablet, capsule, particles, powder or sachet and dry suspensions.
11. The pharmaceutical composition as claimed in claim 1, wherein the excipients are preferably polyvinylpyrrolidone as binder, mannitol as diluent, magnesium stearate as lubricant, sodium lauryl sulphate and beta-cyclodextrin as permeation enhancer and polyethylene glycol as plasticizer.
12. The pharmaceutical composition as claimed in claim 1, wherein the dose to achieve a maximum control of post prandial blood glucose concentration in diabetic patients within 5-60 minutes post - administration.
13. The pharmaceutical composition as claimed in claim 1, wherein said composition produces lowered serum glucose in human patients by at least 5% with in 120 minutes post oral administration.
14. A process for manufacturing an orally administrable solid pharmaceutical composition of a cation-insulin conjugate complex comprising saturated or unsaturated C4 - C12 fatty acids or salts thereof and at least three pharmaceutlcally acceptable excipients selected from the group comprising binders, disintegrants, diluents, lubricants, plasticizers, permeation enhancers and solubilizers.
15. The process as claimed in claim 14, wherein said process comprising steps of:

a) grinding a suitable saturated or unsaturated C4-C12 fatty acids and/or salts of such fatty acid;
b) granulating the resulting fatty acid obtained from step (a) with an organic solvent;
c) air-drying the granules obtained from step (b);

d) rasping the dried granules through a mesh to obtain granules of desired particle size; and
e) blending the fatty acid granules with the cation-insulin conjugate complex with the other excipients to obtain the composition.
16. The process as claimed in claim 14, wherein said process comprising steps of:
a) grinding suitable saturated or unsaturated C4-C12 fatty acids and/or salts of such fatty acid and a binder;
b) suspending the cation-insulin conjugate complex in an organic solvent using the binder to form a wet mass;
c) granulation of the components obtained from step (b) using the binder;
d) rasping the dried granules of step (c); and
e) blending the granules with other excipients to obtain the composition.

17. The process as claimed in claim 15 and 16, wherein the blended mixture is compressed to obtain solid dosage form, preferably tablet form.
18. The process as claimed in claim 15, wherein said organic solvent is selected from a group comprising isopropanol, acetone, methyl alcohol, methyl isobutyl ketone, chloroform, 1-propanol, 2-propanol, acetonitrile, 1-butanol, 2-butanol, ethyl alcohol, cyclohexane, dioxane, ethyl acetate, dimethylformamide, dichloroethane, hexane, isooctane, methylene chloride, tert-butyl alchohol, toluene, carbon tetrachloride, or combinations thereof
19. A 5-500 mg tablet composition of an cation-insulin conjugate complex comprising saturated or unsaturated C4 - C12 fatty acids, fatty acid esters, or salts thereof and at least three pharmaceutically acceptable excipients selected from the group comprising binders, disintegrants, lubricants, plasticizers and permeation enhancers.
20. The 5-500 mg tablet composition as claimed in claim 19, wherein the preferable dosage ranges are selected from a group comprising 50 mg, 100 mg, 150mg, 200mg and 250mg tablet compositions.

21. An orally administrable solid pharmaceutical composition, a process to prepare such composition and a 5- 500 mg tablet composition are substantially as herein described along with accompanying drawings and examples.