DESC:
FIELD OF THE INVENTION
[0001] The present disclosure pertains to the field of an oral delivery system for delivering medication and/or ingredients to a part of a gastrointestinal tract. The invention also relates to a process for preparing the delivery system.

BACKGROUND OF THE INVENTION
[0002] Traditionally, the parenteral route of administration has been widely explored for delivering drugs because it provides a direct route for achieving the drug effect within the body, is free from hepatic first pass effect, requires low drug concentration, can be administered to an unconscious patient when he cannot swallow the medicine, medicines which are destroyed in the gastrointestinal tract can be given etc. There are five commonly used routes of parenteral administration: subcutaneous (SC/SQ), intraperitoneal (IP), intravenous (IV), intradermal (ID), and intramuscular (IM). However, this route of administration also suffers from shortcomings. For example, it is an expensive method of drug administration, requires a skilled person for administration, may cause pain and injury at the site of injection, requires effective sterilization and is a risky route since there are chances of adverse effects or poisoning. Another drawback is that parenteral administration requires the patient to travel to the physician's office resulting in patient inconvenience.
[0003] Accordingly, there remains a need for a safe, effective, and less invasive manner for delivery of therapeutic agents in the body. Compositions and methods that meet these objectives would be critical for improving the treatment of various disorders.
[0004] Alternatively, the oral route is simple, convenient, and the most preferred route for administration of a therapeutic agent. However, many active ingredients in healthy food, oral drugs, or the like use a type of formulation that disintegrates in the stomach. The gastrointestinal (GI) tract has several regions sharply demarcated by local pH ranging from 5.5 to 8.2. The distal ileum further uniquely contains a region where the usual pH is between 7.3 and 8.2. Notably, this area is relatively devoid of degradation pathways for antigens such as vaccine constructs, yet far more sensitive to their presence. Many antigens are degraded by the acid and proteolytic conditions of the stomach and anterior GI tract, conditions which make oral vaccination impractical to nearly impossible from a technical point of view. Thus, the distal ileum and the area of the ileal brake, which is optimal for a controlling sensor for nutritional balance, also uniquely contains both the optimum pH conditions for vaccination (stability of antigenic substance) and contains numerous specialized sensing cells (such as Peyer's Patches), that help to define the immune system response to the foreign invader pathogens and in some cases, tumors. In view of the above, a limiting factor in the development of peptide drugs is the relative ineffectiveness when given orally. Almost all peptide drugs are parenterally administered, although parenterally administered peptide drugs are often connected with low patient compliance as mentioned above.
[0005] Several known techniques have been developed for circumventing the drawbacks associated with both parenteral and oral route of administration.
[0006] US9259456B2 refers to an oral dosage form for treating diabetes mellitus, comprising insulin, soybean trypsin inhibitor (SBTI), and EDTA, wherein said insulin, soybean trypsin inhibitor (SBTI), and EDTA are all in a water-free oily solution comprising an omega-3 fatty acid. US9259456B2 also refers to a method for oral administration of insulin to a subject, comprising orally administering insulin along with a protease inhibitor such as soybean trypsin inhibitor. Protease inhibitors enhance the ability of omega-3 fatty acids to protect insulin and facilitate its absorption in the intestine. Protease inhibitors such as cysteine protease inhibitors, serine protease inhibitors (serpins), trypsin inhibitors, threonine protease inhibitors, aspartic protease inhibitors, metallo protease inhibitors. Protease inhibitors comprising of suicide inhibitor, transition state inhibitor, or chelating agents can be used. However, none of these protease inhibitors succeeded as an additive in application of polypeptide drug delivery at a commercial scale, as they are toxic and may exhibit several side-effects. Protease inhibitors are associated with potential health risks and utilization of these protease inhibitors should be avoided. Apart from facing these limitations, they are associated with high manufacturing cost, heterogeneity, regulatory hurdles, challenges as to achieving selective inhibition, and requirement of high doses for effective activity (Approaches for enhancing oral bioavailability of peptides and proteins, Renukuntla J et al., Int J Pharm. 2013, 447, 75-93) making its utilization non-viable.
[0007] EP3006045B1 discloses a combination of trace elements such as copper or zinc with a pharmaceutically acceptable reducing agent, optionally in combination with a mucosal absorption enhancer that results in a surprisingly high and advantageous oral bioavailability of different peptide or protein drugs. However, copper and zinc are associated with many metabolic pathways in mammals, and hence, utilization thereof for a long-term therapy may results in negative interactions.
[0008] WO2013009849A1 refers to a method of eliciting protective immunity against Norovirus in a human comprising administering parenterally to the human no more than a single dose of a vaccine composition comprising genogroup I Norovirus virus-like particles (VLPs), wherein said composition induces at least a three-fold increase in Noro virus-specific serum antibody titer as compared to the titer in the human prior to administration of the composition, and wherein said genogroup I Norovirus VLPs comprise a capsid protein derived from a genogroup I viral strain. However, parenteral route of administration suffers from drawbacks as mentioned above. Additionally, similar drawbacks have also been observed with parenteral administration of insulin. Daily injection of insulin causes considerable suffering for patients. Side effects such as lipodystrophy at the site of the injection, lipatrophy, lilpohypertrophy, and occasional hypoglycemia are known to occur. In addition, subcutaneous administration of insulin does not typically provide the fine continuous regulation of metabolism that occurs normally with insulin secreted from the pancreas directly into the liver via the portal vein.
[0009] WO2002074336A2 refers to an influenza vaccine preparation for intradermal administration use, which ensures the delivery of an influenza vaccine antigen to an upper layer part of human skin to highly increase an HI antibody titer in an earlier stage in the prevention of influenza infection, and which is highly safe. It also teaches regarding an influenza vaccine preparation which can be administered using an intradermal administration device equipped with a needle tube, wherein a needle tip of the needle tube is so designed as to ensure a vaccine preparation to be administered to an upper layer part of skin; and a method for preventing influenza using the preparation.
[00010] US 6489346 B1 teaches the use of large amounts of buffers to prevent the degradation of acid labile drugs. For instance, certain compositions of omeprazole contain 1100 mg of sodium bicarbonate (equivalent to 300 mg of sodium) and oral suspension contains 1680 mg of sodium bicarbonate (equivalent to 460 mg of sodium). Such formulations utilize the concept of microenvironment pH and hence a large quantity of alkali is required to neutralize the acid in the stomach to protect the uncoated PPI from acid degradation and maintain intragastric pH>4 for a period of about 18 hours. The recommended daily intake of sodium is 2,400 mg for a normal person and, these amounts should be taken into consideration by anyone on a sodium-restricted diet. Also, sodium bicarbonate is contraindicated in patients with metabolic alkalosis and hypocalcemia. Such compositions weigh about 1.5-2.0 g making it difficult to swallow and hence leading to patient non-compliance. Furthermore, since, the amount of buffer depends on the pKa of the drug used, the amount of alkali required to make an immediate release composition of Pantoprazole or Rabeprazole, may be more than that required for Omeprazole. Moreover, sodium bicarbonate used in the composition has poor stability properties and decomposes by converting to carbonate and such; the decomposition is accelerated by agitation or heat. Hence, such compositions comprising large amounts of buffers are also not suitable for long term usage.
[00011] There is, therefore, a need in the art to develop simple, safe, efficient, and cost-effective pharmaceutical compositions that can deliver gastric labile drugs to more than one location in the gastrointestinal tract while providing protection from gastric acid degradation upon ingestion. It would also be desirable to provide a delivery system and methods that provide medication or ingredients having diverse physical properties (e.g., solid, liquid, gas, or dispersion), which may or may not be properly combined or stored together into a unitary structure for usage in a single dosage form. The present disclosure satisfies the existing needs, as well as others and alleviates the shortcomings of the traditional pharmaceutical compositions and delivery techniques. Accordingly, the inventors of the present invention have invented a delivery system which not only eliminates patient discomfort and inconvenience, but also preserves medication or ingredients from inactivation. It is also an object to provide a delivery system which can be used in the treatment of a plurality of conditions, wherein it is desired to control both the release rate and site of release of the medication or ingredients.
OBJECTIVE OF THE INVENTION:
[00012] The main objective of present invention is to provide a delivery system that affords protection to medication or ingredients which undergo degradation in the acidic pH of the stomach.
[00013] Another objective of the present invention is to provide an efficient delivery system for intestinal application which permits an improved release profile and/or an improved longterm stabilization with regard to the active ingredients.
[00014] Another object of the present disclosure is to provide a delivery system that increases oral bioavailability of the active ingredients.
[00015] Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said delivery system.
[00016] Yet another objective of the present invention is to provide a delivery system that exhibits long shelf-life.
[00017] Another objective of the present invention is to provide a dosage form that can be self-administered as against the current injectable route which requires professional assistance.
[00018] An objective of the present invention is to provide a capsule-in-capsule delivery system with a larger outer capsule and at least one inner relatively smaller capsule.
[00019] An objective of the present invention is to provide a delivery system comprising a larger outer capsule and at least one inner relatively smaller capsule, wherein the larger outer capsule comprises the inner capsule, and wherein the outer capsule is an enteric release capsule which dissolves in the intestine when ingested to release a first medication or ingredient and the inner capsule which may be an enteric release capsule which dissolves in the intestine when ingested, to release a second medication or ingredient into the intestine. Either medication or ingredients may be present as a liquid or as a solid and the encapsulating materials are selected to be non-reactive both with the contents of the capsule and with their intended local external environment.
[00020] Another objective of the present invention is to provide a biologic or vaccine in the inner capsule and a buffering agent in the outer capsule.
[00021] Yet another objective of the present invention is to provide a biologic or vaccine in the inner capsule and an oil in the outer capsule.
[00022] Another objective of the present invention is to provide a biologic or vaccine in the inner capsule and a moisture absorption agent in the outer capsule.
[00023] One objective of the present invention is to protect the biologic or vaccine which is filled in the inner capsule, from gastric degradation by co-administration of protein and peptide drugs with protease inhibitors in the outer capsule.
[00024] Yet another objective is to increase the bioavailability of the biologic or vaccine in inner capsules by adding mucoadhesive materials which increases the contact/residence time of the biologic with the absorptive epithelium at the site of application in the outer capsule.
[00025] An objective is to increase the bioavailability of the biologic or vaccine placed in the inner capsule by using surfactants or tight junction-opening permeation enhancers in the outer capsule to make the mucosal barrier more permeable.
SUMMARY OF THE INVENTION
[00026] The present invention provides a delivery system which delivers one or more prophylactic agent like small molecules like a drug or an API (active pharmaceutical ingredient), vaccines or therapeutic agents like biologic, to at least one location in the gastrointestinal tract to treat various conditions and improve health.
[00027] In a preferred aspect, the delivery system is a capsule-in-capsule system with a larger outer capsule and at least one inner relatively smaller capsule.
[00028] In one aspect of the present invention, provides a delivery system comprising a larger outer capsule and at least one inner relatively smaller capsule, wherein the larger outer capsule comprises the inner capsule, and wherein the outer capsule is an enteric release capsule which does not dissolve in the stomach, but dissolves in the intestine when ingested to release a medication or ingredient and the inner capsule may be an enteric release capsule which also dissolves in the intestine when ingested to release the same or different medication or ingredient into the intestine. Either medication or ingredients may be present as a liquid or as a solid and the encapsulating materials are selected to be non-reactive both with the contents of the capsule and with their intended local external environment.
[00029] In one aspect, a small molecule or biologic or vaccine is present in the inner capsule and a buffering agent is present in the outer capsule.
[00030] In yet another preferred aspect, a small molecule, a biologic or vaccine is present in the inner capsule and an oil is present in the outer capsule.
[00031] In a further aspect, a small molecule or a biologic or vaccine is present in the inner capsule and a moisture absorbing agent is present in the outer capsule to prevent assimilation of moisture
[00032] In another aspect, the biologic or vaccine is protected from gastric degradation and enhanced absorption by co-administration of protein and peptide drugs with protease inhibitors in the outer capsule.
[00033] In a further aspect, the bioavailability of the biologic or vaccine filled in inner capsule is increased by using mucoadhesive materials which increases the contact/residence time of the biologic with the absorptive epithelium at the site of application in the outer capsule.
[00034] In an aspect, the bioavailability of the biologic or vaccine in inner capsule is increased by placing surfactants or tight junction-opening permeation enhancers in the outer capsules to make the mucosal barrier more permeable. Permeation enhancers function by widening the space between adjacent epithelial cells (the paracellular space), which is normally too small to accommodate biologics.
[00035] In another aspect, the present invention provides a therapeutically effective, non-toxic, and safe delivery system with no side effects.
[00036] In one aspect of the present invention, there is provided a delivery system which enables simultaneous administration of one or more medication or ingredients which increases patient compliance by reducing the number of doses to be administered.
[00037] In a further aspect of the present invention, one or more medication or ingredients are filled in separate capsules to avoid cross interaction between the two ingredients.
[00038] In a preferred aspect, the present invention provides a convenient process for preparation of the targeted delivery system.
DRAWINGS
[00039] The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations and are not intended to limit the scope of the present disclosure.
[00040] Figure 1 discloses a standard plot of diclofenac sodium in 0.1N HCl (n=3± s.d).
[00041] Figure 2 discloses a standard plot of diclofenac sodium in pH 6.8 phosphate buffer (n=3± s.d).
DETAILED DESCRIPTION OF THE INVENTION
[00042] The following is a detailed description of embodiments of the present disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[00043] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[00044] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[00045] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[00046] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[00047] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[00048] All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00049] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[00050] Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[00051] The present invention provides a delivery system for delivery of one or more medication or ingredients to at least one location in the gastrointestinal tract.
[00052] In a preferred embodiment, the delivery system is a capsule-in-capsule system with a larger outer capsule and at least one inner relatively smaller capsule.
[00053] In an embodiment, the present invention provides a delivery system comprising a larger outer capsule and at least one inner relatively smaller capsule, wherein the outer capsule is an enteric release capsule which dissolves in the intestine when ingested to release a first medication or ingredient and the inner capsule is a delayed or enteric release capsule which dissolves in the intestine when ingested to release a second medication or ingredient into the intestine. Either medication or ingredients may be present as a liquid or as a solid and the encapsulating materials are selected to be non-reactive both with the contents of the capsule and with their intended local external environment.
[00054] In an embodiment, the delivery system is selected from any or a combination of tablets (coated or uncoated tablets), capsules (soft gelatin capsules, hard gelatin capsules, HPMC capsules, or HPMCP capsules or starch or acrylic capsules), a capsule-in-capsule, tablet-in-capsule, lozenges, troches, ovules, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets, effervescent tablets, multi-particulate dosage forms and the likes. However, any or a combination of oral pharmaceutical dosage form(s), as known to or appreciated by a person skilled in the art, can be utilized to serve its intended purpose, as laid in the present disclosure, without departing from the scope and spirit of the present invention.
[00055] As used herein the term “capsule” refers to a conventional soft or hard capsule intended for oral administration to a human or animal being. When reference is made herein to “capsule” it refers to the outer or inner capsule or the outer capsule comprising the inner capsule unless the context indicates otherwise. Generally, the term “capsule” refers to both empty and filled capsules whereas “shell” specifically refers to an empty capsule.
[00056] In another embodiment, the inner capsule and/or outer capsule can be formed with an acid resistant material or composition which is resistant to gastric juice but soluble in the small intestine. The acid resistance prevents the capsule from dissolving within the stomach and allows the capsule to pass and dissolve further within the intestine. The capsule sections can be formed from a material that dissolves in the intestine or dissolves in a liquid environment such that it begins to dissolve as soon as it enters the intestine of a human. Accordingly, in another embodiment, the outer capsule may be formed with an acid resistant material or composition which is stable at the pH less than 4 in the stomach and configured to dissolve at a pH greater than 6 in the small intestine and the inner capsule fully encapsulated by said outer capsule, may be formed with an acid resistant material or composition which is stable at the pH less than 4 in the stomach and configured to dissolve at a pH greater than 6 in the intestine.
[00057] Such gastric juice-resistant, but small intestine-soluble shell materials are known per se to the person skilled in the art. For this purpose, the shell can comprise one or more compositions selected from the group consisting of poly(dl-lactide-co-glycolide, chitosan (Chi) stabilized with PVA (poly-vinylic alcohol), a lipid, an alginate, carboxymethylethylcellulose (CMEC), hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose, color con, food glaze and mixtures of hydroxypropylmethyl cellulose and ethyl cellulose, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, and copolymers of methacrylic acid and ethyl acrylate or mixtures of the foregoing.
[00058] The capsule shell of the present invention may also be made of bacterial or yeast-derived film-forming polymers (exo-polysaccharides) such as pullulan. Other typical exo-polysaccharides are xanthan, acetan, gellan, welan, rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan, dextran, and mixtures thereof.
[00059] The shapes of the capsules may be ellipsoidal, spherical, cylindrical with rounded ends, irregular, or as otherwise needed for an intended application.
[00060] Medication or ingredients inside the capsule may be in solid, liquid or paste form, depending on use.
[00061] In one embodiment, a small molecule, a biologic or vaccine is present in the inner capsule and a buffering agent is present in the outer capsule.
[00062] Acid labile drugs can be easily destroyed in the acidic environment of the stomach, making absorption of such drugs through the stomach difficult. Therefore, buffering agents can be used, which immediately buffer the internal environment of the body and increase the stability of acid labile drugs inside the body.
[00063] In a preferred embodiment, the capsule formulation may comprise buffering agents selected from, but is not limited to, an amino acid, an alkali metal salt of an amino acid, aluminium hydroxide, aluminium hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminium magnesium hydroxide, aluminium hydroxide/magnesium hydroxide co-precipitate, aluminium hydroxide/sodium bicarbonate coprecipitate, aluminium glycinate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminium hydroxide gel, L-arginine, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium gluconate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium phosphate, trometamol, and mixtures thereof. In particular, the buffering agent can be sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, and mixtures thereof.
[00064] In yet another preferred embodiment, a small molecule, a biologic or vaccine is present in the inner capsule and an oil is present in the outer capsule.
[00065] In a preferred embodiment, the capsule formulation may comprise a pharmaceutically or edible oil. The “pharmaceutically or food-acceptable oil” in the present invention (in the present specification, sometimes simply referred to as “oil”) reduces or substantially prevents acid (acid solution, for example, gastric juice in vivo) from penetrating into the capsule through the capsule membrane and coming into contact with the active ingredients in the capsule. That is, although the oil is not limited, it exhibits a hydrophobicity with respect to the aqueous phase (including gastric acid which is an acidic solution), so that it exists separately without mixing with the aqueous phase to form an oil phase.
[00066] In yet another preferred embodiment, the oil is an edible oil selected from the group consisting of plant oil, animal oil, fish oil and mineral oil. The oil is an edible oil, and said edible oil is selected form the group consisting of medium-chain triglyceride, safflower oil, olive oil, soybean oil, linseed oil, rice germ oil, wheat germ oil, coconut oil, corn oil, cottonseed oil, palm oil, palm nucleus oil, peanut oil, rapeseed oil, sesame oil, sunflower oil, almond oil, cashew oil, hazelnut oil, macadamia nut oil, pecan oil, pine nut oil, pistachio oil, walnut oil, calabash seed oil, buffalo gourd oil, pumpkin seed oil, watermelon seed oil, acai berry extract, blackcurrant seed oil, borage seed oil, evening primrose oil, amaranth oil, apricot oil, apple seed oil, artichoke oil, avocado oil, ben oil, cape chestnut oil, carob oil, cohune palm oil, coriander oil, false flax oil, grape seed oil, hemp oil, kapok seed oil, mustard oil, okra seed oil (hibiscus oil), papaya oil, poppyseed oil, prune kernel oil, quinoa oil, camellia oil, thistle oil, tomato oil, saw palmetto oil, krill oil, borage oil, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), vitamin A oil, vitamin D oil, vitamin E oil, vitamin K oil, lecithin, and any combination thereof.
[00067] In a further embodiment, a small molecule, a biologic or vaccine is present in the inner capsule and a moisture absorbing agent is present in the outer capsule.
[00068] Moisture has an impact on the formulation stability by chemically or physically influencing the active ingredient. Many APIs and excipients are hygroscopic in nature and need to be protected from moisture. Specific attention needs to be given when formulating such ingredients to prevent degradation due to hydrolysis. Therefore, moisture absorption agents that absorb water in the place of the active to prevent its degradation can be used.
[00069] In a preferred embodiment, the capsule formulation may comprise moisture absorption agents such as magnesium aluminium silicate, carboxymethylcellulose, calcium carbonate, calcium silicate, potato starch, corn starch, rice starch, wheat starch, or cassava starch.
[00070] In another embodiment, the biologic/vaccine is protected from gastric degradation by co-administration of protein and peptide drugs with protease inhibitors. In a preferred embodiment, the protease inhibitors are selected from the group consisting of ritonavir, saquinavir, indinavir, nelfinavir, lopinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, darunavir, which are HIV protease inhibitors, and protease inhibitors for SARS-CoV-2 etc.
[00071] In yet another embodiment, the biologic/vaccine is protected from gastric degradation by modifying the chemical structures of biologics to improve their stability in gastro-intestinal fluids.
[00072] In a further embodiment, the bioavailability of the biologic/vaccine is increased by using mucoadhesive materials which increases the contact/residence time of the biologic with the absorptive epithelium at the site of application. In a preferred embodiment, the mucoadhesive materials are selected from the group consisting of chitosan, poly(acrylic acid) and its weakly cross-linked derivatives, alginate, poly(methacrylic acid), sodium carboxymethyl cellulose etc.
[00073] In an embodiment, the bioavailability of the biologic/vaccine is increased by using surfactants or tight junction-opening permeation enhancers to make the mucosal barrier more permeable. Permeation enhancers function by widening the space between adjacent epithelial cells (the paracellular space), which is normally too small to accommodate biologics.
[00074] In a preferred embodiment, the surfactants are selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric surfactants, non-ionic surfactants, biosurfactants and mixtures thereof.
[00075] In a preferred embodiment, the permeation enhancers are selected from the group consisting of Salcaprozate sodium (SNAC) and sodium caprate (C10) which are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules.
[00076] In a preferred embodiment, the present invention provides a delivery system with the medication present in the inner capsule and an excipient present in the outer capsule.
[00077] In one embodiment, the delivery system further includes optionally any or a combination of one or more pharmaceutically acceptable excipients (also referred to as ingredients) such as but not limited to carriers, diluents, fillers, disintegrants, oil, buffering agents, moisture absorption agents, lubricating agents, binders, glidants, surfactants, absorbents, colorants, pigments, stabilizers, preservatives, flavours, antioxidants, solvents and/or absorption enhancers. In another embodiment, the delivery system, optionally, further includes one or more pharmaceutically acceptable additives such as vitamin E, histidine, microcrystalline cellulose (MCC), mannitol, starch, sorbitol and/or lactose.
[00078] Pharmaceutically acceptable excipients (also referred to as ingredients) include, but are not limited to, pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, fillers or extenders such as microcrystalline cellulose, powdered cellulose, compressible sugar, starch (e.g., corn starch or potato starch), pregelatinized starch, fructose, mannitol, dextranes, other sugars such as, siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, calcium lactate or mixtures thereof; binders such as cellulose derivatives (e.g. hypromellose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose), polyvinylpyrrolidone, gelatin, lactose, sucrose, acacia, polyethylene glycol, polymethacrylates, hydroxypropylcellulose, pregelatinized starch and sodium alginate; disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; absorption enhancers such as quaternary ammonium compounds; absorbents such as kaolin and bentonite clay; lubricants such as talc, solid polyethylene glycols, aluminium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate, magnesium stearate, tin stearate, sodium lauryl sulfate, lecithins, mineral oils, stearic acid, silicones, and mixtures thereof; and colouring agents. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[00079] In a preferred embodiment, a biologic is present in the inner capsule.
[00080] In another preferred embodiment, a vaccine is present in the inner capsule.
[00081] In an embodiment, the vaccine / biologic is selected from the group consisting of insulin, peptides, proteins, amino acids, oncological biologics, vaccines for TB, Covid 19, polio, yellow fever and the like.
[00082] In an embodiment, the pharmaceutical compositions can be formulated by any techniques known to or appreciated by a person skilled in the art, to serve its intended purpose, as laid in the present disclosure, without departing from the scope and spirit of the present invention.
[00083] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual subject may be varied and will depend upon a variety of factors including the activity of the specific peptide or protein drug employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy. For example, 3 times/ per day, 2 times/ per day, 1 time/ per day. Depending on the blood stability, a less frequent administration frequency (for example, once / week, once / month, etc.) may be selected.
[00084] In yet another embodiment, delivery system can be used to deliver a plurality of drugs for the treatment of multiple conditions or for the treatment of a particular condition. In use, such embodiments allow a patient to forgo the necessity of having to take multiple medications for a particular disease, illness, or condition. A disease, illness, or condition may affect one or more organ systems in an animal or human. Organ systems may include, for example: (1) autonomic, (2) cardiovascular, (3) neurological, (4) gastro-intestinal, (5) respiratory, (6) renal system, (7) psychiatric, (8) endocrine, (9) gynaecologic, (10) urologic, (11) immunologic, (12) bone and joint systems, (13) ear, nose, and throat, (14) dermatologic, (15) hematologic, (16) infectious defence and (17) nutrition and metabolism. In an animal or human who may be suffering from one disease, illness or condition, it is common to also be suffering from a disease, illness or condition affecting one or more of the other organ system(s). These concomitant diseases, illnesses or conditions occurring within a single animal or human are often labelled as “co-morbidities,” a term often shortened and referred to as “co-morbid.”

[00085] Advantages of the present invention:
[00086] The capsule delivery system and the process of the present invention have the following characteristics which help overcome the drawbacks associated with already available formulations.
1) The delivery system allows drug delivery to be targeted to two different regions of the GI tract.
2) Orally delivered drugs are exposed to various environments in the process of pharmaceutical absorption. Firstly, some drugs, may be degraded by a variety of digestive enzymes present in the stomach. Second, the value of pH is different throughout the gastrointestinal (GI) tract and varies from highly acidic in the stomach (pH 1–3) to neutral or slightly alkaline in the duodenum (pH 6) and along the jejunum and ileum (pH 6–7.5). Certain drugs tend to get inactivated (degraded) by gastric pH, which reduces their absorption. The delivery system of the present invention protects medication or ingredients from inactivation by gastric acid and digestive enzymes which may inactivate the drug.
3) It offers high drug loading, a wide range of release rate designs, and fine tuning of these release rates. It has less risk of dose dumping, less inter-and intra-subject variability, high degree of dispersion in the digestive tract thus minimizing the risks of high local drug concentrations.
4) The thick mucus layer and short transit time in the stomach limits drug absorption. The present invention increases drug bioavailability by delivering the medication or ingredients to the intestine where the surface area is larger, and membranes are more permeable.
5) Since drug bioavailability and absorption is improved, drug dosing frequency is reduced which in turn minimizes side effects and improves patient compliance.
6) Cheap, safe, and easily available GRAS components have been used.
7) Affords oral delivery of vaccines and biologics which otherwise are administered as injections.

EXAMPLES

[00087] Example 1:
Enteric capsule in capsule formulations of diclofenac sodium were prepared to evaluate the ability of various formulation strategies in protecting the contents of inner capsules from the gastric environment. The formulation strategies included addition of moisture absorbing agent or alkalinizing agent or edible oil in the outer capsules. Inner capsules of Size 3 were of two varieties – HR (regular HPMC (hydroxypropyl methylcellulose)) and HX (delayed release) whereas the outer enteric capsules were of Size 0. Powder blend equivalent to 50 mg diclofenac sodium was filled in size 3 capsules. Size 3 capsules were then filled in Size 0 capsules. Also, the blends containing calcium carbonate (moisture absorbing agent) or sodium phosphate (alkalanizer) or safflower oil (edible oil) were filled in the outer capsules. All the capsules were band- sealed with HPMCP (hypromellose phthalate) solution. The formulations were subjected to in vitro drug release testing as per the USP monograph for diclofenac sodium enteric coated tablets. All the formulations except the ones filled with oil showed less than 5% drug release at the end of 2h in 0.1N HCl. The formulation filled with oil in outer capsules showed more than 10% release in 0.1N HCl. A variable drug release was obtained in pH 6.8 phosphate buffer at the end of 4 h from different formulations. Size 3 HX band sealed inner capsules showed 2.86% release in acidic medium and 37% release in 4h in phosphate buffer.
Methods
1. Drug standardization
Standard plots of diclofenac sodium in 0.1N HCl and pH 6.8 Phosphate buffer Diclofenac sodium : 10 mg was dissolved in sufficient methanol and made up the volume to 10 mL. (Stock A) The stock A solution was suitably diluted with 0.1N HCl to obtain standard solutions ranging from 4 PPM to 32 PPM. The solutions were analysed spectrophotometrically (Labman, Model – LMSP-UV1900) at the ?max of 278nm. The absorbance values were plotted against the concentration to obtain the standard plot and its equation.
Stock A solution was suitably diluted with Phosphate buffer pH 6.8 to obtain standard solutions ranging from 4 PPM to 32 PPM. The standard solutions were analysed spectrophotometrically (Labman, Model – LMSP-UV1900) at the ?max of 276nm. The absorbance values were plotted against the concentration to obtain the standard plot and its equation.

2. Inner capsule formulation
• Preparation of blend containing drug (50 mg dose), and appropriate excipients.
The powder blend of diclofenac sodium was prepared using the following formula

Table 1: Composition of diclofenac sodium powder blend for filling into Size 3 capsules
No. Ingredient Weight/ capsule (mg) Weight (g)/ 300 capsules
1 Diclofenac sodium 50 15
2 Microcrystalline Cellulose (Avicel PH 102) 93 27.9
3 Croscarmellose sodium (Ac-Di-Sol) 5 1.5
4 Colloidal silicon dioxide (Aerosil 200) 4 1.2
5 Magnesium stearate 3 0.9
Total fill weight 155 46.5
The drug and all the excipients except magnesium stearate were passed through 40# sieve and mixed in a polybag for 5 minutes. Magnesium stearate was added to the blend in polybag and mixed for 2 minutes.
The blend was filled in size 3 HX capsules using a hand filling machine (capacity -100 capsules). Out of 200 filled capsules, 100 capsules were band sealed using HPMCP solution.
The similar blend was filled in size 3 HR capsules to obtain 100 capsules.

• Average weight and weight variation test
Size 3 -HX and HR capsules (10 No. each) were subjected to average weight and weight variation test.

3. Capsule in capsule formulations

a. Formulation containing moisture absorbing agent
Size 3 HX, Size 3HX band sealed, and Size 3 HR capsules were filled in Size 0 enteric capsules. Along with Size 3 capsules, the powder blend containing calcium carbonate (moisture absorbing agent) was also filled into the Size 0 capsules using the hand filling machine. The composition of the powder blend was as follows

Table 2: Composition of blend containing moisture absorbing agent for filling into Size 0 enteric capsules
No. Ingredient Weight/ capsule (mg) Weight (g)/ 100 capsules
1 Calcium carbonate 50 5
2 Microcrystalline Cellulose (Avicel PH 102) 50 5
3 Colloidal silicon dioxide (Aerosil 200) 3 0.3
4 Magnesium stearate 2 0.2
Total fill weight 105 10.5
The size 0 capsules were then band sealed with HPMCP solution using a band sealing machine.
b. Formulation containing alkalinizing agent

Size 3 HX, Size 3HX band sealed, and Size 3 HR capsules were filled in Size 0 enteric capsules. Along with Size 3 capsules, the powder blend containing disodium hydrogen phosphate (alkalinizing agent) was also filled into to the Size 0 capsules using the hand filling machine. The composition of the powder blend was as follows

Table 3: Composition of blend containing alkalinizing agent for filling into Size 0 enteric capsules

No. Ingredient Weight/ capsule (mg) Weight/ 100 capsules
1 Disodium hydrogen phosphate 10 1
2 Microcrystalline Cellulose (Avicel PH 102) 110 11
3 Colloidal silicon dioxide (Aerosil 200) 3 0.3
4 Magnesium stearate 2 0.2
Total fill weight 125 12.5

The size 0 capsules were then band sealed with HPMCP solution using a band sealing machine.

c. Formulation containing edible oil
Size 3 HX band sealed and Size 3 HR band –sealed capsules were filled in Size 0 enteric capsules. The capsules were then manually filled with safflower oil (200mg/capsule) and sealed. The capsules were band sealed with HPMCP solution using a band sealing machine.

The capsule formulations were packed in HDPE containers and stored in cool, dry place until further studies.
4. In vitro drug release studies of the capsule in capsule formulations
The capsule formulations were subjected to in vitro release studies using following conditions
Apparatus: USP Type II
Paddle speed – 50 rpm
Stage 1
Medium: 900 ml of 0.1 N HCl maintained at 37°C for 2 h
Sampling and analysis: 5 ml aliquots taken at the end of 2 h and analysed spectrophotometrically at 276 nm.
After stage 1 dissolution, 0.1N HCl to be removed from the dissolution flask and replaced with 900 ml pH 6.8 Phosphate buffer to proceed with stage 2 dissolution
Stage 2
Medium: 900 ml of pH 6.8 Phosphate buffer at 37°C for 4h
Sampling and analysis: 5 ml aliquots taken at 45, 90, 150, 240 min; diluted suitably and analysed spectrophotometrically at 276 nm
Sinkers were used during drug release studies to avoid the floating of capsules
5. Results
Inner capsule formulation
The diclofenac sodium powder blend could be filled uniformly in Size 3 capsules using hand filling machine. The average weight and weight variation of filled capsules has been shown in table 4. Both Size 3 HX and HR capsules showed <10% weight variation.
Table 4: Weight variation of Size #3 HX and HR capsules
Sr. No. Capsule weight in mg of size 3 HX capsules (±) % weight variation of size 3 HX capsules Capsule weight in mg of size 3 HR capsules (±) % weight variation of size 3 HR capsules
1 212 4.22 214 1.80
2 209 2.75 214 1.80
3 206 1.27 210 0.09
4 204 0.29 196 6.75
5 205 0.78 214 1.80
6 209 2.75 217 3.23
7 199 2.16 208 1.04
8 209 2.75 209 0.57
9 192 5.60 199 5.32
10 189 7.08 221 5.13
Avg. Weight -203.4 mg Avg. Weight -210.2mg

Capsule in capsule formulations
Three types of capsule in capsule formulations were prepared. One contained calcium carbonate as a moisture absorbing agent which is expected to prevent the ingress of gastric fluid into inner capsules. 2nd formulation contained disodium phosphate in the outer capsule to protect the active of inner capsule by providing alkaline microenvironment. The third formulation contained safflower oil in the outer capsule to prevent the ingress of gastric fluid in inner capsules. All the three formulations were band sealed with HPMCP solution to provide enteric protection to the contents.
In vitro drug release studies of the capsule in capsule formulations
Drug release studies were performed using the pharmacopoeial method recommended for release studies of diclofenac sodium enteric coated tablets. Sinkers supplied by Electrolab Ltd were used to prevent floating of the capsules. The results are presented in the following tables
Table 5: In vitro drug release from capsules containing calcium carbonate
Time (min) In vitro release (%)*
HX capsules HX capsules- band sealed HR capsules
0.1 N HCL
120 2.21±0.1 4.95±0.29 5.82±1.87
pH 6.8 Phosphate buffer
45 10.08±0.82 10.66±8.97 23.47±12.44
90 13.93±2.20 15.44±10.03 26.10±10.60
150 18.26 ± 3.94 18.48±11.06 27.01±8.19
240 36.10±6.63 29.12± 9.14 37.54±7.45
*The data shown is mean ± s.d of n=6

Table 6: In vitro drug release from capsules containing Disodium hydrogen phosphate
Time (min) In vitro release (%)*
HX capsules HX capsules- band sealed HR capsules
0.1 N HCL
120 5.72±0.17 4.55±1.09 6.18±0.19
pH 6.8 Phosphate buffer
45 3.16±0.19 4.66±0.97 15.91±12.24
90 8.51±4.11 7.14±3.52 21.90±12.86
150 15.98±9.51 17.18±8.06 25.14±12.87
240 28.54± 10.89 29.52± 6.89 36.23±10.45
*The data shown is mean ± s.d of n=6

Table 7: In vitro drug release from capsules containing safflower oil
Time (min) In vitro release (%)*
HX capsules- band sealed HR capsules- band sealed
0.1 N HCL
120 10.64±4.22 3.39±0.42
pH 6.8 Phosphate buffer
45 61.83±25.04 65.91±12.38
90 66.71±16.73 81.29±14.80
150 74.49±20.13 96.03±14.72
240 - -
*The data shown is mean ± s.d of n=6

Table 8: In vitro drug release from size 3 inner capsules
Time (min) In vitro release (%)*
Size 3 HX band sealed inner capsules Size 3 HR inner capsules
0.1 N HCL
120 2.86 ± 0.22 6.17±0.44
pH 6.8 Phosphate buffer
45 26.70 ± 1.28 87.35±4.35
90 30.51 ± 1.35 94.54±3.89
150 32.95 ± 0.65 -
240 37.09 ± 2.6 -
*The data shown is mean ± s.d of n=6

Key Observations

• More than 10% of oil filled capsules showed leakage after band sealing.
• Oil filled formulations showed the highest drug release in 0.1N HCl as well as in pH 6.8 phosphate buffer.
• Formulations containing calcium carbonate as a moisture absorbing agent showed least release of 2% in 0.1N HCl and remained intact along with the intact band seal. The formulations sustained the drug release in pH 6.8 buffer.
• Most of the enteric capsules containing either calcium carbonate or disodium phosphate retained the contents within the shells after 4h of dissolution in pH 6.8 buffer. Upon removing from sinkers, the shells burst into powders.
• Drug release in pH 6.8 buffer showed higher standard deviation for all the enteric formulations. This could be because of variable dissolution of Size 0 enteric capsules.
• Size 3 HR inner capsules when subjected to release studies showed complete disintegration in acidic medium. However, only 6% drug dissolution was observed which could be attributed to poor solubility of diclofenac sodium in 0.1 N HCl. (3.5 µg/mL) The formulation showed >85% release in pH 6.8 Phosphate buffer within 45 minutes.
• Size 3 HX band sealed capsules remained intact in acidic medium for two hours and showed only 2.8% drug release whereas in in pH 6.8 buffer, the release was about 37 % at the end of 4h.

Conclusion
Size 3 HX band sealed inner capsules were able to provide protection to the contents from acidic medium and sustain the release of the API in alkaline medium. Size 0 enteric capsules containing size 3 capsules and other protecting agents like moisture protectant (calcium carbonate) or alkalinizing agent (disodium phosphate) provided acid-protection and sustained release. However, capsules containing safflower oil showed > 10% drug release in acidic medium and faster and complete drug release within 4 hours in pH 6.8 phosphate buffer. The trials of oil filled capsules need to be repeated using flow- fit variety of enteric capsules.
[00088] While the foregoing description discloses various embodiments of the disclosure, other and further embodiments of the invention may be devised without departing from the basic scope of the disclosure.
,CLAIMS:1.) An oral capsule-in-capsule delivery system configured for an enteric release, said system comprises an outer acid resistant capsule adapted to receive an acid resistant inner capsule such that the size of the inner capsule is smaller with respect to the outer capsule;
wherein said outer capsule comprises at least one ingredient selected from the group of an active ingredient, at least one buffer, at least one moisture absorbing agent, at least one edible oil and at least one protease inhibitor; and
wherein said inner capsule comprises at least one active ingredient in solid, gel or liquid form.
2.) The delivery system as claimed in claim 1, wherein said outer acid resistant capsule is stable at a pH in the range of 1 to 4 and dissolves at a pH in the range of 5 to 7.5.
3.) The delivery system as claimed in claim 1, wherein said inner acid resistant capsule is stable at a pH in the range of 1 to 4 and dissolves at a pH in the range of 5 to 7.5
4.) The delivery system as claimed in claim 1, wherein said outer acid resistant capsule comprises at least one ingredient selected from the group of poly(dl-lactide-co-glycolide, chitosan (Chi) stabilized with PVA (poly-vinylic alcohol), a lipid, an alginate, carboxymethylethylcellulose (CMEC), hydroxypropylmethylcellulose succinate, cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropylmethyl cellulose, ethyl cellulose, color con, food glaze and mixtures of hydroxypropylmethyl cellulose and ethyl cellulose, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), shellac, copolymers of methacrylic acid and ethyl acrylate, copolymers of methacrylic acid and ethyl acrylate, bacterial or yeast-derived film-forming polymers (exo-polysaccharides), xanthan, acetan, gellan, welan, rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan, tamarind gum, curdlan and dextran.
5.) The delivery system as claimed in claim 1, wherein said at least one buffer is selected from the group of an amino acid, an alkali metal salt of an amino acid, hydroxides of aluminium, magnesium and co precipates there of, also carbonates / bicarbonates/ hydroxides / phosphates/ hydrogen phosphates / poly phosphates of calcium, sodium, potassium, magnesium and combination and mixtures thereof.
6.) The delivery system as claimed in claim 1, wherein said at least one protease inhibitor is selected from the group of ritonavir, saquinavir, indinavir, nelfinavir, lopinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, and darunavir.
7.) The delivery system as claimed in claim 1, wherein said at least one moisture absorbing agent is selected from the group of magnesium aluminium silicate, carboxymethylcellulose, calcium carbonate, calcium silicate, potato starch, corn starch, rice starch, wheat starch and cassava starch.