Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
  • A61K9/2846—Poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2893—Tablet coating processes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats

Definitions

• the present invention generally relates to the field of oral drug delivery, and in particular to pharmaceutical compositions for enhancing absorption and increasing bioavailability of therapeutic agents that demonstrate poor absorption and low bioavailability in conventional oral drug delivery systems.
• the invention further relates to methods for making and using the disclosed pharmaceutical compositions.
• Oral drug delivery is one of the most common and accepted routes of drug administration.
• many therapeutic agents are poorly delivered via the oral route.
• biologically active macromolecules such as proteins, peptides, polysaccharides and nucleic acids often cannot be administered orally due to the combined effects of enzyme degradation, poor absorption or instability.
• oral formulations of many classes of small molecule drugs such as cyclosporine, fenofibrate, lipid lowering statins,
• permeation enhancers are commonly used to enhance the absorption of drugs that are otherwise poorly absorbed (for a review, see B.J. Aungst, J. Pharm. Sci., 2000, 89(4):429-442). Numerous examples of permeation enhancers that are known to improve transdermal or transmucosal absorption are disclosed in U.S. Patent Nos.
• absorption enhancers in oral formulations are often limited due to associated toxicity.
• a successful pharmaceutical product containing an absorption enhancer is a colon suppository formulation of ampicillin, which is commercially available in Sweden (DOKTACILLINTM, Astra Lakemedel AB).
• a formulation containing 25 mg sodium caprate as a permeation enhancer was reported to increase the maximum serum concentration (C max ), area under the serum concentration-time curve (AUC) and urinary recovery of ampicillin 2.6-, 2.3- and 1.8-fold, respectively, compared to ampicillin alone (T. Lindmark et al , Pharm. Res., 1997, 14(7):930-935).
• One object of the present invention is to provide a non-toxic pharmaceutical composition capable of enhancing the absorption and/or bioavailability of a poorly absorbed therapeutic agent. Another object is to provide a pharmaceutical composition for enhanced drug delivery that can modulate the pharmacokinetic profile of a therapeutic agent and is inexpensive and relatively easy to manufacture.
• the invention provides a pharmaceutical composition for drug delivery comprising a solid dosage form containing an effective amount of a therapeutic agent, a permeation enhancer and a pharmaceutically acceptable excipient, to form a core, which is coated by a bioadhesive layer containing a bioadhesive polymer.
• the above pharmaceutical composition can be further coated with an enteric material to prevent content release in the stomach and permit release at a preferred site in the gastrointestinal tract such as the small intestine.
• the invention provides a pharmaceutical composition for drug delivery comprising a solid dosage form containing an effective amount of a therapeutic agent, a permeation enhancer and a pharmaceutically acceptable excipient to form a core, which is coated by a bioadhesive layer containing a bioadhesive polymer, and further coated by an impermeable or semi-permeable layer having an opening capable of directing a substantially unidirectional release of the therapeutic agent and the permeation enhancer from the solid dosage form.
• the pharmaceutical composition can be further coated with an enteric material to prevent content release in the stomach and permit release at a preferred site in the gastrointestinal tract such as the small intestine.
• the therapeutic agent and the permeation enhancer have substantially equivalent relative rates of release from the solid dosage form.
• the present pharmaceutical composition allows regional, restricted and substantially synchronous release of a therapeutic agent and a permeation enhancer, thereby improving the absorption of the therapeutic agent using a significantly reduced amount of the permeation enhancer compared to the prior art.
• the invention provides a pharmaceutical composition that is capable of modulating the pharmacokinetic profile of a therapeutic agent.
• the release kinetics of the therapeutic agent and the permeation enhancer can be modulated by a different composition and/or ratio of components in the core matrix, or by a different composition, ratio, and/or thickness of the bioadhesive polymer layer, or by a different composition, ratio, and/or thickness of the impermeable or semi-permeable layer, to provide a burst or immediate release, or an extended or sustained profile, depending on the desired therapeutic effect.
• the invention provides a method for making a
• composition for drug delivery comprising fabricating a solid dosage form comprising an effective amount of a therapeutic agent, a permeation enhancer and a pharmaceutically acceptable excipient; coating the solid dosage form with a bioadhesive layer comprising a bioadhesive polymer; and optionally coating the solid dosage form with an impermeable or semi-permeable layer comprising an opening capable of directing a substantially unidirectional release of the therapeutic agent and the permeation enhancer from the solid dosage form.
• the order of applying the bioadhesive polymer layer and the impermeable or semi-permeable layer is reversed.
• the method further comprises coating the composition with an enteric layer.
• the invention provides a method of treating a subject in need of a therapeutic treatment by administering the present pharmaceutical composition to the subject by the oral, nasal, buccal, sublingual, rectal or vaginal routes of administration.
• FIG. 1 illustrates the synchronous release of exenatide and absorption enhancer sodium caprate from tablets coated with layers of hydroxypropyl methylcellulose (HPMC) and enteric polymer EUDRAGIT® L30D-55.
• FIGS. 2 A and 2B show the effect of a unidirectional release layer on the release kinetics of exenatide and sodium caprate from tablets coated with layers of HPMC and enteric polymer.
• FIGS. 3A and 3B show the effect of a bioadhesive layer on the bioavailability of exenatide in the presence of 100 and 400 mg sodium caprate and an enteric layer.
• FIG. 4 demonstrates the effect of sodium caprate amount on the bioavailability of exenatide in the presence of an AA1 layer and an enteric layer.
• FIG. 5 shows the effect of a unidirectional release layer on the bioavailability of exenatide in the presence of 50 mg caprate, an HPMC layer, and an enteric layer.
• FIG. 6 shows the effect of a unidirectional release layer on the bioavailability of exenatide in the presence of 100 mg caprate, an HPMC layer, and an enteric layer.
• FIG. 7 shows the effect of an enteric layer on the bioavailability of exenatide in the presence of 200 mg sodium caprate, an HPMC layer, and a unidirectional release layer.
• FIG. 8A illustrates the release kinetics of insulin in 0.01N HC1 (first 2 hrs) and simulated intestinal fluid (SIF), pH 6.8 (hours 3-7) in the presence of 200 mg sodium caprate, an HPMC layer, and a unidirectional release layer.
• FIGS. 8B and 8C demonstrate the effects of oral insulin treatment on blood glucose and serum insulin concentration, respectively, in somatostatin treated dogs.
• FIG. 9 compares the effects of two oral insulin formulations on blood glucose levels in somatostatin treated dogs.
• the first formulation was a two-layer tablet that included 200 mg sodium caprate, an HPMC layer and a unidirectional release layer.
• the second formulation was a three-layer tablet that included 200 mg sodium caprate, an HPMC layer, a unidirectional release layer, and an enteric outer layer.
• FIGS. lOA-C compare stability of exenatide in various solid formulations following storage at 60°C (FIG. 10A), 25°C at 92.5% relative humidity (FIG. 10B), and 4500 lux photo exposure (FIG. IOC) for 0, 5 and 10 days.
• FIG. 11 shows the effect of oral insulin administration on blood glucose in normal dogs.
• the insulin formulation used for this experiment was a three-layer tablet that included 100 sodium caprate, an HPMC layer, a unidirectional release layer, and an enteric layer.
• FIG. 12 compares exenatide absorption mediated by unidirectional release layers produced by manual and laser ablation processes.
• the exenatide formulations used for this experiment were two-layer tablets that included 200 mg sodium caprate, an HPMC layer containing the L30D-55 enteric material, and a unidirectional release layer prepared either manually or by laser ablation.
• FIG. 13 illustrates the dose-dependent effect of oral insulin administration (25U, 25U x 2, and 50U) on blood glucose levels in somatostatin treated dogs.
• the insulin formulations used for this experiment were two-layer tablets that included 200 mg sodium caprate, an HPMC layer containing the L30D-55 enteric material, and a unidirectional release layer.
• FIGS. 14A and 14B demonstrate the effect of bioadhesive polymer content in the bioadhesive layer on the kinetics of exenatide release and absorption in normal dogs.
• the exenatide formulations used for this experiment were two-layer tablets that included 100 mg sodium caprate, an HPMC layer containing 65% or 80% HPMC and the L30D-55 enteric material, and a unidirectional release layer prepared by laser ablation.
• composition or “pharmaceutically acceptable formulation” refers to a composition or formulation that allows for the effective distribution of a moiety or a compound in the physical location most suitable for its desired activity.
• the term "effective amount” or “therapeutically effective amount” of an active agent refers to a nontoxic but sufficient amount of the agent to provide the desired therapeutic or prophylactic effect to most patients or individuals. It is commonly recognized that the effective amount of a pharmacologically active agent may vary depending on the route of administration, as well as the age, weight, and sex of the individual to which the drug or pharmacologically active agent is administered. It is also commonly recognized that one of skill in the art can determine appropriate effective amounts by taking into account such factors as metabolism, bioavailability, and other factors that affect plasma levels of an active agent following administration within the unit dose ranges disclosed further herein for different routes of administration.
• the term "pharmaceutically acceptable” refers to a non-toxic, inert composition that is physiologically compatible with humans or other mammals.
• the term "pharmaceutical excipient” refers to a material such as an adjuvant, a carrier, pH-adjusting and a buffering agent, a tonicity adjusting agent, a wetting agent, a preservative, and the like.
• the terms "subject,” “individual,” “host,” and “patient” are used interchangeably to refer to an animal that is the object of treatment, observation and/or experiment.
• the term “animal” includes vertebrates and invertebrates, such as fish, shellfish, reptiles, birds, and, in particular, mammals.
• the term “mammal” encompasses, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees and apes, and, in particular, humans.
• the term “treating” refers to any and all uses which remedy or prevent a diseased or infected state or symptoms, or otherwise deter, hinder, retard, or reverse the progression of a disease/infection or other undesirable symptoms.
• the terms “treating” and “therapeutic” refer to any improvement or amelioration of any consequence of disease; full eradication of disease is not required.
• Amelioration of symptoms of a particular disorder refers to any lessening of symptoms, whether permanent or temporary, that can be attributed to or associated with administration of a therapeutic composition of the present invention.
• administering refers to any suitable method of providing a composition of the present invention of the invention to a subject.
• the pharmaceutical compositions of the present invention may be administered by the oral, nasal, buccal, sublingual, rectal or vaginal routes of administration.
• the pharmaceutical compositions may be formulated in suitable dosage unit formulations appropriate for each route of administration.
• solid dosage form refers to any dosage form that is in the form of a solid including, but not limited to, tablets, caplets, capsules including those made from hard or soft materials such as gelatin or natural or synthetic gelatin substitutes, lozenges, combinations thereof and the like.
• permeation enhancer refers to an agent that improves the rate of transport of a pharmacologically active agent across the mucosal surface.
• a permeation enhancer increases the permeability of mucosal tissue to a therapeutic agent.
• permeation enhancers increase the rate at which the therapeutic agent permeates through membranes and enters the bloodstream.
• Enhanced permeation effected through the use of permeation enhancers can be observed, for example, by measuring the flux of the pharmacologically active agent across animal or human membranes.
• an "effective" amount of a permeation enhancer refers to an amount that will provide a desired increase in mucosal membranes permeability to provide, for example, the desired absorption and/or bioavailability of a selected compound.
• bioadhesive generally refers to any adhesive that interfaces with living tissue and/or biological fluid.
• bioadhesive layer refers to a solid layer that is intended to be adhered to a mucosal tissue of a subject.
• the bioadhesive layer contains at least one "bioadhesive polymer,” which may be selected, without limitation, from carbomer, polycarbophil, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymefhyl cellulose, polyvinyl alcohol, sodium hyaluronate, chitosan, alginate, xanthum gum, acrylic polymers and derivatives and mixtures thereof.
• bioadhesive polymer which may be selected, without limitation, from carbomer, polycarbophil, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymefhyl cellulose, polyvinyl alcohol, sodium hyaluronate, chitosan, alginate, xanthum gum, acrylic polymers and derivatives and mixtures thereof.
• impermeable or semi-permeable refers to a material that is sufficiently impermeable to physiological fluids as well as ingredients contained within the drug delivery system such that the migration of such fluids and ingredients into or out of the system through the impermeable or semi-permeable material is so low as to have substantially no adverse impact on the function of the system.
• substantially unidirectional release means that more than about 50%, 60%, 70%, preferably more than about 80%, more preferably more than about 90%) and most preferably more than about 95% of the therapeutic agent and the permeation enhancer comprised in the solid dosage form is released from the solid dosage form in the same single direction that is defined by an opening in the impermeable or semipermeable layer.
• substantially equivalent relative rates of release means that the release of the therapeutic agent and the permeation enhancer from the solid dosage form is substantially synchronous, i.e. the difference between the fraction (%) of the therapeutic agent released at any given time and the fraction of the permeation enhancer released at the same time is less than about 50%, 40%, 30%>, preferably less than about 20%, more preferably less than about 10% and most preferably less than about 5%.
• enteric coating refers to a mixture of pharmaceutically acceptable excipients which is applied to the solid dosage form and which prevents release of the active ingredient(s) in the mouth, esophagus or stomach, but which rapidly and completely releases the drug when the dosage form passes into the proximal portion of the lower gastrointestinal tract.
• the enteric layer preferably comprises about 1 to 15%, more preferably about 3 to 12%, and most preferably about 6 to 10% by weight based on the combined weight of the solid dosage form and the coating.
• the enteric coating polymer may be selected, without limitation, from cellulose acetate phthalate (EUDRAGIT® S or L), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, shellac and methacrylic acid copolymers.
• the thickness of the coating is selected to provide the desired release rate, which is dependent on the nature and thickness of the coating.
• plasticizer refers to a material that may be
• Plasticizers include, but are not limited to, citrate esters (e.g., triethylcitrate, triacetin), low molecular weight polyalkylene oxides (e.g., polyethylene glycols,
• plasticizer can be present in a concentration from about 0.1 % to about 25%, preferably about 0.5-15% or about 1-20% by weight of the pharmaceutical composition. Additional examples of plasticizers can be found in M. & I. Ash, THE HANDBOOK OF PHARMACEUTICAL ADDITIVES (3 rd ed., Synapse Information Resources, Inc., 2007).
• range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 3, from 2 to 4, from 2 to 5, from 2 to 6, etc., as well as individual numbers within that range, for example, 1 , 2, 3, 4, 5 and 6. This applies regardless of the breadth of the range.
• the invention provides a pharmaceutical composition for drug delivery comprising a solid dosage in the form of tablet, patch, disc or powder comprising an effective amount of a therapeutic agent, a permeation enhancer and a pharmaceutically acceptable excipient to form a core, which is further coated with a bioadhesive layer containing a bioadhesive polymer.
• the pharmaceutical composition is further coated with an enteric material to permit release at a preferred site in the gastrointestinal tract.
• the permeation enhancer was sodium caprate and the drug tested was exenatide, which is a 39-amino acid peptide (marketed by Amylin and Eli Lilly as BYETTA® for the treatment of type 2 diabetes).
• exenatide which is a 39-amino acid peptide (marketed by Amylin and Eli Lilly as BYETTA® for the treatment of type 2 diabetes).
• BYETTA® 39-amino acid peptide
• the amount of sodium caprate needed to achieve a significant absorption enhancement was in the range of 275-550 mg in dogs (U.S. Patent Application Pub. No. 2008/0275001).
• a smaller amount of sodium caprate (115-120 mg) in an enteric coated formulation was found to be ineffective in the same animal model (Burcham et al, Pharm. Res., 1995, 12(12):2065-2070).
• the invention provides a pharmaceutical composition for drug delivery comprising a solid dosage in the form of tablet, patch, disc or powder containing an effective amount of a therapeutic agent, a permeation enhancer and a pharmaceutically acceptable excipient to form a core, which is further coated with a bioadhesive layer containing a bioadhesive polymer, which is then further coated with an impermeable or semi-permeable layer having an opening capable of directing a substantially unidirectional release of the therapeutic agent and the permeation enhancer from the solid dosage form.
• the pharmaceutical composition can be further coated with an enteric material to permit release at a preferred site in the gastrointestinal tract.
• this composition can further reduce the amount of a permeation enhancer without adversely affecting the absorption enhancement.
• U.S. Patent Nos. 4,772,470 and 5,827,525 disclose a patch or oral bandage for buccal drug administration.
• an oral patch format comprising a site selecting layer, a drug, an adhesive layer and impermeable layer is disclosed in U.S. Patent No. 7,097,851 and a number of non-patent publications (e.g., S. Eaimtrakarn et al., Biomaterials, 2002, 23(1): 145-152; S. Eaimtrakarn et al, Intl. J. Pharm., 2003, 250(1): 111-1 17; and S.L. Tao & T.A.
• Example 6 The effect of the unidirectional release layer on the absorption and bioavailability of exenatide in the presence of sodium caprate is illustrated in Example 6.
• exenatide absorption in dogs was minimal, consistent with the earlier reports in the art (U.S. Patent No. 7,605,123).
• the coating material can be either impermeable or semi-permeable.
• permeation enhancers often require a certain minimal concentration to be effective.
• concentration of sodium caprate needed to achieve a permeation enhancing effect is estimated to be at least 10-13 mM (see E.K.
• formulations comprising an additional impermeable or semi-permeable layer and having an extended release profile compared to simpler formulations have demonstrated a relatively high level of absorption enhancement.
• unidirectional release formulations may be used to modulate a therapeutic agent's pharmacokinetic profile by varying the thickness of the impermeable or semi-permeable layer, the content and nature of the plasticizer used to modify the impermeable or semi-permeable material, and the size of the opening.
• the therapeutic agent and the permeation enhancer are released from the pharmaceutical composition in a substantially synchronous fashion.
• the pharmaceutical composition extends the time of release and allows sustained absorption.
• the therapeutic agents to be delivered comprise those that are poorly absorbed in the gastrointestinal tract and belong to class III or IV compounds according to the Biopharmaceutics Classification System (BCS) classification (see Food and Drug Administration, "Guidance for Industry: Waiver of In Vivo Bioavailability and
• the poorly absorbed therapeutic agent is selected from the group consisting of an acetylcysteine, an acamprosate, an acyclovir, an albendazole, an alcuronium, an alendronate, an alfuzosin, an alprazolam, an alprostadil, an amikacin, an aminobisphosphonate, an amiodarone, an amitriptyline, an amlodipine, an amoxacilline, an amphetamine, an amphotericin B, an ampicillin, an artemether, an artesunate, an aspirin, an atazanavir, an atenolol, an atomoxetine, an atorvastatin, an atropine, an azithromycin, an AZT, a bacitracin, a beclometasone, a benzathine benzylpenicillin, a benzylpenicillin, a biperiden
• chlorphenamine a chlorpromazine, a cilastatin, a cimitidine, a ciprofloxacin, a
• clarithromycin a clofazimine, a clomipramine, a clonidine, a clopidogrel, a clotrimazole, a cloxacillin, a cyclophosphamide, a cyclosporine, a cytarabine, a d-9-tetra hydro cannabinol, a dacarbazine, a dactinomycin, a danazol, a dapsone, a daunorubicin, a deferoxamine, a desipramine, a dexamethasone, a didanosine, a diethylcarbamazine, a digoxin, a
• dihydroergotamine a diltiazem, a dimercaprol, a dolargin, a domperidone, a domperidone, a dopamine, a doxazosin, a doxetaxel, a doxorubicin, a duloxetine, an efavirenz, an
• eflornithine an enalapril, an enprostil, an epinephrine, an ergometrine, an erlotinib, an erythromycin, an esomeprazole, an estradiol, an eszopiclone, an etoposide, an ezetimibe, a famotidine, a felodipine, a fenofibrate, a fentanyl, a fexofenadine, a finasteride, a flucytosine, a fludrocortisones, a fluorouracil, a fluoxetine, a fluphenazine, a flurbiprofen, a fluticasone, a fluvastatin, a formoterol, a furosemide, a gabapentin, a ganciclovir, a gemcitabine, a gentamicin, a glib
• griseofulvin a haloperidol, a hydralazine, a hydrochlorothiazide, a hydrocortizone, a hydroxocobalamin, an ibandronic acid, an ibuprofen, an imipenem, an imipramine, an indinavir, an ipratropium bromide, an irbesartan, an irinotecan, an isoniazid, an isosorbide dinitrate, an itraconazole, a kanamycin, a ketoconazole, a ketoprofen, a labetalol, a latanoprost, a levamisole, a levodopa, a lidocaine, a lisinopril, a loperamide, a lopinavir, a losartan, a lovastatin, a lumefantrine, a mebendazole, a medroxypro
• suxamethonium a tacrolimus, a tadalafil, a tamoxifen, a tegaserod, a telmisartan, a temozolomide, a tenidap, a tenofovir, a tenofovir disoproxil fumarate, a terfenadine, a testosterone, a tetracaine, a tetracycline, a timolol, a tiotropium, a triamcinalone, a triclabendazole, a trovafloxacin, a tubocurarine, a ubiquinone, a valaciclovir, a valproic, a valsartan, a vancomycin, a vardenafil, a vecuronium, a venlafaxine, a verapamil, a vinblastine, a vincris
• the therapeutic agent comprises one that is selectively absorbed at a specific absorption site including, without limitation, the upper small intestine.
• the therapeutic agents include, without limitation, riboflavin, levodopa, metformin, and furosemide.
• the therapeutic agent comprises a biologically active macromolecule selected from a protein, a peptide, a polysaccharide, a nucleic acid, a lipid, a carbohydrate or a combination thereof.
• the protein is selected from the group consisting of an anti-thrombin, an albumin, an alpha- 1 -proteinase inhibitor, an anti-hemophilic factor, a coagulation factor, an antibody, an anti-CD20 antibody, an anti-CD52 antibody, an anti- CD33 immunotoxin, a DNase, an erythropoietin, a factor IX, a factor VII, a factor VIII, a follicle stimulating hormone, a granulocyte colony-stimulating factor (G-CSF), a pegylated G-CSF, a galactosidase alpha or beta, a glucagon, a glucocerebrosidase, a granulocyte- macrophage colony-stimulating factor (GM-CSF), a choriogonadotropin, a hepatitis B antigen, a hepatitis B surface antigen, a hepatitis
• the peptide is selected from the group consisting of an ACTH, an anti-angiogenic peptide, an adamtso statin, an adiponectin, an adipokinetic hormone, an deiponutrin, an adipose desnutrin, an adrenomedullin, an agouti-related protein, an alarin, an allatostatin, an amelogenin, a calcitonin, an amylin, an amyloid, an agiopoietin, an angiotensin, an anorexigenic peptide, an anti-inflammatory peptide, an anti-diuretic factor, an anti-microbial peptide, an apelin, an apidaecin, a RGD peptide, an atrial natriuretic peptide, an atriopeptin, an auriculin, an autotaxin, a bombesin, a
• corticotropin release factor a cortistatin, a coupling factor, a defensin, a delta sleep inducing peptide, a dermorphin, a vasopressin, a desamino-vasopressin, a diuretic hormone, a dynorphin, an endokinin, an endomorphin, an endorphin, an endo statin, an endothelin, an enkephalin, an enterostatin, an exendin, an exendin-4, an erythropoietic peptide, an epithelia growth factor, a fat targeted peptide, a galanin, a gastric inhibitory peptide, a gastrin, a gastrin releasing peptide, a ghrelin, a glucagon, a glucagon-like peptide, a glutathione derivative, a gluten exorphin, a growth hormone releasing factor, a GM-CSF inhibitory
• pancreastatin a peptide YY, a physalaemin-like peptide, a secretin, a somatostatin, a sperm- activating peptide, a substance P, a syndyphalin, a thrombospondin, a thymopoietin, a thymosin, a thyrotropin-releasing hormone, a transforming growth factor, a tuftsin, a tumor necrosis factor antagonist or related peptide, a usrechistachykinin, a urocortin, a urotensin antagonist, a valorphin, a vasotocin, a VIP, a xenopsin or related peptide, and any
• the peptides may be produced by recombinant technology, chemical synthesis or extracted from biological sources.
• the peptides include modified analogs or derivatives of wild type proteins.
• the origin of the peptides may be human or from other species.
• the biologically active macromolecule is a vaccine against a microorganism selected from a group consisting of an adenovirus, anthrax, BCG, botulinum, cholera, diphtheria toxoid, diphtheria & tetanus toxoids, diphtheria tetanus & pertussis, haemophilus B, hepatitis A, hepatitis B, influenza, encephalitis, measles, mumps, rubella, meningococcal, plague, pertussis, pneumococcal, polio, rabies, rotavirus, rubella, smallpox, tetanus toxoid, typhoid, varicella, yellow fever, bacterial antigens and any combination thereof.
• a microorganism selected from a group consisting of an adenovirus, anthrax, BCG, botulinum, cholera, diphtheria tox
• the biologically active macromolecule is an allergen selected from a group consisting of house dust mite, animal dander, molds, pollens, ragweed, latex, vespid venoms and insect-derived allergens, and any combination thereof.
• the biologically active macromolecule may comprise a combination of macromolecules with similar biological functions, including, for example, a combination of a wild type molecule with its chemically or biologically modified analogs.
• GLP-1 glucagon-like peptide 1
• liraglutide taspoglutide
• albiglutide albiglutide
• lixisenatide and exenatide and its analogs examples include, without limitation, glucagon-like peptide 1 (GLP-1) and its analogs, liraglutide, taspoglutide, albiglutide, lixisenatide and exenatide and its analogs, and any combination thereof.
• the therapeutic agent is selected from exenatide, a 39- amino acid peptide (marketed by Amylin and Eli Lilly as BYETTA® for the treatment of type 2 diabetes) and salts and functional derivatives such as pegylated exenatide, exenatide fusion proteins such as albumin, transferring, XTEN, Fc fusions, and fatty acid modified derivatives thereof.
• exenatide a 39- amino acid peptide (marketed by Amylin and Eli Lilly as BYETTA® for the treatment of type 2 diabetes) and salts and functional derivatives such as pegylated exenatide, exenatide fusion proteins such as albumin, transferring, XTEN, Fc fusions, and fatty acid modified derivatives thereof.
• the permeation enhancer is selected from the group consisting of a fatty acid, a medium chain glyceride, a surfactant, a steroidal detergent, an acyl carnitine, an alkanoyl choline, an N-acetylated amino acid, and esters, salts and derivatives thereof.
• the permeation enhancer comprises a fatty acid, including, without limitation, butyric, caproic, caprylic, pelargonic, capric, lauric, myristic, palmitic, stearic, arachidic, oleic, linoleic, linolinic acid, their salts, derivatives and any combination thereof.
• the permeation enhancer comprises a glyceride of a fatty acid, including, without limitation, butyric, caproic, caprylic, pelargonic, capric, lauric, myristic, palmitic, stearic, arachidic, oleic, linoleic, linolinic acid, their salts, derivatives and any combination thereof.
• the glyceride may be a monoglyceride, a diglyceride, or triglyceride, and the fatty acid may comprise the same or different fatty acids.
• the permeation enhancer comprises a fatty chain having 8 to 14 carbon atoms.
• the permeation enhancer comprises a bile acid or salt, including conjugated or un-conjugated bile acids, such as cholate, deoxycholate, taurocholate, glycocholate, taurodeoxycholate, ursodeoxycholate, tauroursodeoxycholate,
• conjugated or un-conjugated bile acids such as cholate, deoxycholate, taurocholate, glycocholate, taurodeoxycholate, ursodeoxycholate, tauroursodeoxycholate,
• the permeation enhancer comprises a metal chelator, such as EDTA, or EGTA, a surfactant, such as sodium dodecyl sulfate, polyethylene ethers or esters, polyethylene glycol- 12 lauryl ether, salicylate, polysorbate 80 (Tween 80®), nonylphenoxypolyoxyethylene, dioctyl sodium sulfosuccinate, saponin, palmitoyl carnitine, lauroyl 1-carnitine, dodecyl maltoside, acyl carnitines, alkanoyl choline, and any combination thereof.
• a metal chelator such as EDTA, or EGTA
• a surfactant such as sodium dodecyl sulfate, polyethylene ethers or esters, polyethylene glycol- 12 lauryl ether, salicylate, polysorbate 80 (Tween 80®), nonylphenoxypolyoxyethylene, dioctyl sodium
• permeation enhancers include 3'-nitrobenzoate, zoonula occulden toxin, fatty acid ester of lactic acid salts, glycyrrhizic acid salt, hydroxyl beta-cyclodextrin, N-acetylated amino acids such as sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, and chitosan, salts and derivatives of these compounds, and any combination thereof.
• the permeation enhancer comprises compounds that selectively target and open tight-junctions (e.g., chitosan and its derivatives).
• the permeation enhancer is capric acid, or a salt or derivative thereof.
• the present invention provides pharmaceutical compositions comprising, inter alia, a pharmaceutically acceptable excipient.
• the pharmaceutical composition may be in the form of capsules, tablets, pellets, patches, or discs. Suitable excipients and their formulations are known in the art and are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (21 st ed., Lippincott Williams & Wilkins, 2005), relevant sections of which are incorporated herein.
• the pharmaceutically acceptable excipients comprise the materials that assist the dispersion of carriers.
• the pharmaceutical excipients comprise a disintegrant.
• the pharmaceutical excipients comprise polyplasdone, croscarmellose, crospovidone, sodium starch glycolate,
• hydroxypropyl cellulose and any combination thereof.
• the pharmaceutical compositions may include other components, such as buffers, preservatives, nonionic surfactants, solubilizing agents, absorption enhancers, stabilizing agents, emollients, lubricants and tonicity agents.
• the composition may be formulated to achieve controlled release of the drugs.
• the pharmaceutical compositions may be in a form suitable for oral use, for example, as tablets, troches, lozenges, or hard or soft capsules.
• Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents such as sweetening agents, flavoring agents, coloring agents and preserving agents, e.g. to provide pharmaceutically stable and palatable preparations.
• the excipients used in a tablet may include, for example, inert diluents or fillers, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, microcrystalline cellulose, sucrose, mannitol, and sorbitol; granulating or binding agents such as polyvinyl pyrrolidone, polyethylene glycol, or hydroxypropyl
• the excipients comprising the core formulation include:
• the amount of permeation enhancer, particularly sodium caprate, in the formulation is about 400 mg, about 300 mg, about 200 mg, about 100 mg, about 50 mg, or about 25 mg, preferably about 200 mg, about 100 mg, or about 50 mg, and more preferably about 100 mg.
• the content of sodium caprate ranges between about 25-300 mg, about 50-200 mg, or about 100-200 mg.
• HPMC hydroxypropylmethyl cellulose
• Macromolecular drugs incorporated in this invention are often highly potent, and the drug content in the core formulation is low, at about 1%, about 0.1% or about 0.01%.
• Low dose formulations such as these often face considerable challenges in quality control aspects, including stability, content uniformity, and analytical methods. It is often necessary to devise process to ensure stability of the therapeutic agent while maintain content uniformity.
• High dose drug formulations tend to present different challenges compared with low dose formulations, such as difficulties in terms of compactability and flowability.
• the formulation may further comprise calcium phosphate nanoparticles as described in U.S. Patent Application Pub. No. 2005/02341 14, U.S. Serial No. 12/434,557, and PCT Pub. Nos. WO 2005/084637 and WO 2009/135190, all of which are incorporated herein by reference in their entireties.
• compositions of the present invention may also be any pharmaceutical compositions of the present invention.
• pharmaceutical compositions of the present invention may also be any pharmaceutical compositions of the present invention.
• compositions can be prepared by mixing the pharmaceutical composition with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient include, without limitation, cocoa butter and polyethylene glycols.
• compositions of the present invention may also be any pharmaceutical compositions of the present invention.
• pharmaceutical compositions of the present invention may also be any pharmaceutical compositions of the present invention.
• compositions for the administration of the compounds of the invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy.
• the core pharmaceutical composition of the present invention is coated with a bioadhesive layer comprising a bioadhesive polymer.
• the bioadhesive layer is coated on, and in direct contact with, the solid dosage form. In other embodiments, there may be one or more intermediate layers between the solid dosage form and the bioadhesive layer. In some embodiments, an impermeable or semipermeable layer is positioned between the solid dosage form and the bioadhesive layer. Alternatively, the bioadhesive layer may be positioned between the solid dosage form and the impermeable or semi-permeable layer.
• the bioadhesive layer comprises a bioadhesive polymer that can adhere to the desired target site such as the gastrointestinal tract.
• the bioadhesive polymer may comprise, without limitation, carbomer, polycarbophil, chitosan, alginate, thiomer, gelatin, hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolindone, fumaric anhydride oligomer, polyesters, polyacrylates, polysaccharides, modified dextrans, sodium hyaluronate, pectin, xanthan gum, as well as their salts, derivatives and mixtures.
• the bioadhesive layer comprises hydroxypropyl methylcellulose (HPMC) or polycarbophil AA1.
• the bioadhesive layer comprises a composite of materials, such as a bioadhesive polymer, a plasticizer, or other materials to module the release rate. It is desirable to have high content of bioadhesive materials. In some embodiments, the content of a bioadhesive polymer comprises above about 50%, above about 65%, above about 75%, above about 80%, or above about 90%.
• the bioadhesive layer may further comprise an enteric material, such as cellulose acetate phthalate (EUDRAGIT® S or L), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid copolymers, shellac, their salts and derivatives, and any combination thereof.
• enteric material such as cellulose acetate phthalate (EUDRAGIT® S or L), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid copolymers, shellac, their salts and derivatives, and any combination thereof.
• enteric material in the bioadhesive layer may preserve integrity of the dosage in the stomach and allow release and absorption in the intestines where pH is raised. It often requires high proportion of enteric material such as about 50% or more in order to maintain acid stability. It is therefore quite surprising to observe the acid stability of the dosage even with enteric material as low as about 10-20%.
• bioadhesive layer ranges between about 5-50%, preferably about 10-35%, and more preferably about 15-25%.
• the bioadhesive layer may further comprise a plasticizer, such as glycerol, triacetin, polyvinyl alcohol, polyethylene glycol, their derivatives, and any combination thereof.
• a plasticizer such as glycerol, triacetin, polyvinyl alcohol, polyethylene glycol, their derivatives, and any combination thereof.
• the plasticizer in the bioadhesive layer ranges between about 1-35%, preferably about 5-25%, and more preferably about 10-15%.
• the bioadhesive layer can be present in a content ranging from about 0.5% to about 10%, preferably about 1 -5%, more preferably about 2-3% by weight of the pharmaceutical composition.
• the thickness of the bioadhesive layer can be modulated to achieve desirable release kinetics and absorption.
• the enteric material dissolves quickly once the desired pH is reached. Since the amounts of enteric material presented in the bioadhesive and enteric layers in the
• compositions do not differ significantly, the dissolution rates between a bioadhesive layer containing enteric material and an enteric layer would be expected to be similar.
• the formulations with enteric material incorporated into the bioadhesive layer reduce the coating requirements and simplify the manufacturing process, thereby reducing the production time and subsequently the cost to produce the desired formulations.
• the impermeable or semi -permeable layer is used to modulate the release kinetics and to further reduce the amount of permeation enhancers required to improve the absorption and bioavailability of poorly absorbed therapeutic agents.
• the impermeable or semi-permeable layer comprises an opening that is capable of directing a substantially unidirectional release of the therapeutic agent and the permeation enhancer from the solid dosage form.
• the size and shape of the opening will necessarily depend on the nature of the solid dosage form and the desired release kinetics. Determining the size of the opening is well within the skill of a person skilled in the art. In some embodiments, the opening may fully cover a single side of a tablet or caplet.
• the opening of the unidirectional release tablet covers about 20-90%, preferably about 40-80%, and more preferably about 50-70% of the area on one side of the tablet.
• the of the unidirectional release tablet opening of the unidirectional release tablet can have any shape, for example, a circle, a triangle, a square, a rectangle, a rhombus, a parallelogram, a trapezium, or any other shape.
• the impermeable or semi-permeable layer comprises one or more hydrophilic polymers and/or one or more hydrophobic polymers.
• hydrophilic polymers include, without limitation, protein-based polymers (for example, gelatin or casein), pectin, agarose (agar), chitosan, carrageenan, starch, dextran,
• methylcellulose calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, cross- linked polymers of sodium carboxymethyl cellulose (for example, croscarmellose sodium), microcrystalline cellulose, efhylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose ethers, cellulose acetate, cellulose acetate phthalate, other cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone (PVP), cross-linked povidone, other vinyl polymers and copolymers, guar gum, poloxamer, polyethylene glycol, polyethylene oxide, polyacrylic acid, polyethers, alkoxy polymers, sodium alginate, xanthan gum, other natural hydrogels or hydrogels derived from natural products, or a combination thereof.
• sodium carboxymethyl cellulose for example, croscarmellose sodium
• microcrystalline cellulose efhylcellulose,
• hydrophobic polymers include, without limitation, ethyl cellulose, polyester (such as polycaprolactone (PCL), polyesteramide (PEA), polyhydroxyalkanoate (PHA), polylactic acid (PLA), polylatic glycolic acid (PLGA), polyhydroxybutyrate-co-hydroxyvalerate (PHBV) and polybutylene succinate adipate (PBSA)), wax and low melting wax, polyethylene and ethylene
• polyester such as polycaprolactone (PCL), polyesteramide (PEA), polyhydroxyalkanoate (PHA), polylactic acid (PLA), polylatic glycolic acid (PLGA), polyhydroxybutyrate-co-hydroxyvalerate (PHBV) and polybutylene succinate adipate (PBSA)
• wax and low melting wax wax and low melting wax
• copolymers ethylene/vinyl acetate, polypropylene, polyurethane, ethylene/vinyl alcohol, polyvinyl alcohol, polyvinyllidene, polyolefin, or any combination thereof.
• the impermeable or semi-permeable layer further contains a solvent or plasticizer which makes the layer more flexible.
• the solvent may be any solvent that is compatible with the impermeable or semi-permeable material, including, for example, water and ethanol.
• plasticizers include, without limitation, citrate esters (e.g., triethylcitrate, triacetin), low molecular weight polyalkylene oxides (e.g., polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols), glycerol, pentaerythritol, glycerol monoacetate, diacetate or triacetate, propylene glycol, sodium diethyl
• citrate esters e.g., triethylcitrate, triacetin
• low molecular weight polyalkylene oxides e.g., polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols
• the impermeable layer comprises an ethyl cellulose polymer in conjunction with a glycerol, polyethylene glycol, or triacetin as plasticizer.
• the semi -permeable layer comprises a cellulose acetate in conjunction with polyethylene glycol, triacetin or glycerol as plasticizer.
• the content of plasticizer in a impermeable or semipermeable layer ranges from 5-40%, preferably 10-30%, or more preferably 15-25%.
• the impermeable or semi-permeable layer can be present in a content ranging from about 0.5% to about 10%, preferably about 1-5%, more preferably about 2-4% by weight of the pharmaceutical composition.
• the impermeable layer may further include other components, such as antiseptic agents, preservatives, and other ingredients to improve the stability of the pharmaceutical composition. Examples of additional plasticizers and components may be found in M. & I. Ash, THE HANDBOOK OF PHARMACEUTICAL ADDITIVES (3 rd ed., Synapse Information Resources, Inc., 2007), relevant sections of which are incorporated herein.
• the formation of a unidirectional opening on a formulation is achieved by a laser ablation process commonly used in the production of osmotic pumps. Unlike osmotic pump tablets, the unidirectional aperture is considerably larger (3-9 mm diameter compared to less than 0.5 mm diameter for a typical 10 mm diameter tablet), and the coating is much thinner. Therefore, different laser source and equipment configurations have to be adapted for the present invention.
• the pharmaceutical composition in this invention comprises a core formulation coated with a bioadhesive layer, and a unidirectional layer may be further coated with a site-selective agent to allow release of the drugs at selected sites in the gastrointestinal tract.
• the site-selective agent comprises a pH sensitive polymer that can dissolve in an environment with certain pH values. Coating with the site-selective agent allows the carrier to selectively expose the adhesive layer to certain regions of the gastrointestinal tract.
• the enteric coating polymer may be selected, without limitation, from cellulose acetate phthalate, EUDRAGIT® S or L, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid copolymers, shellac, their salts and derivatives, and any combination thereof.
• the enteric coating polymer is EUDRAGIT® L30D-55.
• the site-selective agent comprises polymers that can selectively attach to or release in the colon.
• colon selective agents include, but are not limited to, azo polymers and colon degradable polysaccharides such as pectin, amylose, guar gum, xylan, cyclodextrin, dextran, their salts and derivatives, and any combination thereof.
• the thickness of the coating is selected to provide the desired release rate, which is dependent on both the nature and thickness of the coating.
• the enteric layer comprises about 1 to 15%, more preferably about 3 to 12%, and most preferably about 6 to 10%) by weight based on the combined weight of the solid dosage form and the coating.
• the present invention contemplates a variety of solid dosage forms including many different combinations of therapeutic agents, permeation enhancers, bioadhesive layers, semi-permeable or impermeable layers, and/or enteric layers.
• the solid dosage form includes an exendin or an exendin peptide analog as the therapeutic agent and sodium caprate as the permeation enhancer;
• the bioadhesive layer includes HPMC or AA1 as the bioadhesive polymer and EUDRAGIT® L30D-55 as the enteric polymer;
• the semi-permeable layer includes cellulose acetate or ethyl cellulose and an opening allowing unidirectional release.
• the bioadhesive layer comprises at least about 70% bioadhesive polymer by weight of the layer and at least about 5% enteric polymer by weight of the layer.
• the amount of sodium caprate ranges between about 100 and 150 mg.
• the exendin is exendin-4, and the exendin peptide analog is exenatide or one of its salts or functional derivatives.
• the bioadhesive layer includes HPMC as the bioadhesive polymer; the semi-permeable layer includes cellulose acetate and an opening allowing unidirectional release; and the solid dosage is in the form of a tablet.
• the bioadhesive layer includes HPMC as the bioadhesive polymer; the semipermeable layer includes ethyl cellulose and an opening allowing unidirectional release; and the solid dosage is in the form of a tablet.
• the solid dosage form includes an exendin or an exendin peptide analog as the therapeutic agent and sodium caprate as the permeation enhancer;
• the bioadhesive layer includes HPMC or AA1 as the bioadhesive polymer;
• the semi -permeable layer includes cellulose acetate or ethyl cellulose and an opening allowing unidirectional release;
• the enteric layer includes EUDRAGIT® L30D-55.
• the bioadhesive layer comprises at least about 70% bioadhesive polymer by weight of the layer.
• the amount of sodium caprate ranges between about 100 and 150 mg.
• the exendin is exendin-4, and the exendin peptide analog is exenatide or one of its salts or functional derivatives.
• the bioadhesive layer includes HPMC as the bioadhesive polymer; the semi-permeable layer includes cellulose acetate and an opening allowing unidirectional release; and the solid dosage is in the form of a tablet.
• the bioadhesive layer includes HPMC as the bioadhesive polymer; the semi-permeable layer includes ethyl cellulose and an opening allowing unidirectional release; and the solid dosage is in the form of a tablet.
• the present invention provides a method for making the present pharmaceutical composition comprising of the following steps: fabricating a solid dosage form comprising an effective amount of a therapeutic agent, a permeation enhancer and a pharmaceutically acceptable excipient; coating the solid dosage form with a bioadhesive layer comprising a bioadhesive polymer; and optionally coating the solid dosage form with an impermeable or semi-permeable layer comprising an opening capable of directing a substantially unidirectional release of the therapeutic agent and the permeation enhancer from the solid dosage form.
• the order of applying the bioadhesive polymer layer and the impermeable or semi-permeable layer is reversed.
• the method further comprises coating the composition with an enteric layer.
• an aqueous suspension of bioadhesive and impermeable or semi-permeable materials such as ethyl cellulose or EUDRAGIT® L30-D55 may be used.
• the materials may be dispensed directly without solvent.
• polycaprolactone (PCL) or wax may be directly dispensed when heated.
• the pharmaceutical composition of present invention is produced in the form of tablets or caplets.
• the core tablets are formed by compression, commonly achieved with a rotary press.
• the tablet fabrication processes including wet granulation and direct compression, have been amply described and are well known art. (DEVELOPING SOLID ORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Ed. by Qiu et al., Academic Press 2009).
• the development of tablet form for macromolecular drugs remains challenging. Most macromolecular drugs are peptides and proteins, which have delicate structure and are highly unstable.
• direct compression process is an appropriate choice for drugs of acceptable dose such as about 0.5-2 mg.
• the direct compression process in common low dose formulation often is straightforward since the content of the drug is so low that the properties of the tablet such as compactability, flowability and hardness are not affected by the presence of the drug as long as uniformity of content can be assured.
• insulin powder which exhibits small crystal particles and is less hydroscopic, can be incorporated into a direct compression process to manufacture tablets when the particle size of the drug powder is properly controlled.
• the formulation in the present invention presents yet another challenge due to the presence of large proportion of permeation enhancer such as sodium caprate, which exhibits poor compactability and may also cause particle segregation.
• permeation enhancer such as sodium caprate
• the direct compression formulation in the present invention is illustrated in the table below.
• the unit dose is expected to be even lower and/or when drug powder exhibits hydroscopic property, direct compression process is often not recommended due to difficulties in achieving content of uniformity in manufacturing process (Zheng 2009, ibid.)
• the balance between stability and content uniformity can be maintained by a non-solvent granulation process.
• the drug powder is suspended in a fluid medium in which drug is insoluble and the drug particle size can be controlled and monitored by sonication or homogenization.
• Binder may be added in the suspension to promote homogeneity.
• the suspension is added to the excipient mixture as in the commonly practiced granulation process.
• the non-solvent granulation process can help to maintain stability while ensuring content uniformity, as illustrated in Examples 12 and 13.
• the commonly used non-solvents that can be used in the present invention include ethanol, isopropanol, acetone, and ethyl acetate.
• the pharmaceutical composition of the present invention is useful for delivering a drug to a desired mucosal surface.
• the composition may selectively attach to a mucosal surface, and the therapeutic agent and permeation enhancer contained in the solid dosage form will flow from the carrier to the mucosal surface unidirectionally to generate high local concentrations of both.
• the present pharmaceutical composition can enhance the absorption of drug with a low amount of permeation enhancer that is otherwise ineffective.
• the present invention provides a method of delivering a therapeutic using the pharmaceutical composition.
• the present invention provides a method of treating a subject in need of a therapeutic treatment, comprising administering to the subject the pharmaceutical composition disclosed herein, preferably to a mucosal surface.
• the pharmaceutical compositions may be administered to the subject by any means known in the art, including, without limitation, oral, buccal, sublingual, vaginal, and rectal routes. Administration may be systemic or localized.
• the core tablets were fabricated according to the formula listed in Table 1 by compressing the materials with a single tablet press. All the components except exenatide and magnesium stearate were first weighed and mixed thoroughly. Granules were then formed with 15% polyvinylpyrrolidone (PVP) in 25% ethanol as adhesive material and dried at 60°C for 2 hrs. The granules were sieved through a 22-mesh screen and weighed based on the single tablet along with exenatide and magnesium stearate. The composition was mixed and pressed into tablet. All tablets were weighed individually, and those tablets with more than 5% of the average weight were excluded.
• PVP polyvinylpyrrolidone
• Table 1 Core tablet formulations (amounts shown in milligrams).
• the core tablets were further coated with bioadhesive polymers, hydroxypropyl methylcellulose (HPMC) or polycarbophil AA1.
• HPMC hydroxypropyl methylcellulose
• the tablets were coated with a 2% HPMC aqueous solution in a small scale tablet coating machine (BY300A, Yellow Sea Machinery). The weight gain due to the coating was 2% of the tablet weight.
• the tablets were coated with 4% polycarbophil AAl in ethanol with a small tablet coating machine. The weight gain was 3%. Coated tablets were dried at 30°C for 14 hrs.
• the core tablets were subsequently coated with a layer comprising either impermeable or semi-permeable materials.
• the tablets were first covered on one side with adhesive paper to create unidirectional release openings.
• the tablets were coated with either 4% ethyl cellulose in ethanol containing 20% triacetin as plasticizer or 3% cellulose acetate in a mixture of acetone and formic acid (9: 1 v/v) containing 20% polyethylene glycol, MW 2000 (PEG 2000) as plasticizer.
• the tablets were dried at 30°C for 30 min. The weight gain due to the coating was adjusted between 2-5%.
• the adhesive paper was peeled off to expose the unidirectional release openings.
• the tablets were coated with enteric polymer EUDRAGIT® L30D-55.
• the coating mixture contained 200 g L30D-55, 12 g ultrafine talc powder and 6 g polyethylene glycol, MW 6000 (PEG 6000), homogenized in water to a final volume of 400 ml.
• the coating was performed in a small scale tablet coating machine. The weight gain due to the enteric coating was 10% of the tablet weight.
• the tablets were dried at 30°C for 14 hrs.
• Table 2 Release of exenatide and sodium caprate from HPMC and enteric coated tablets.
• Table 3 shows the fractions of exenatide or sodium caprate released from the tablets coated with enteric polymer, cellulose acetate, and HPMC containing 50 mg sodium caprate. The results are also summarized in FIG. 2A. Once again, the release of exenatide and sodium caprate is substantially synchronous, and yet significantly extended compared to the tablets not containing a cellulose acetate layer (maximum release reached at 3 hours vs. 2 hrs).
• Table 3 Release of exenatide and sodium caprate from HPMC, enteric and cellulose acetate (CA) coated tablets.
• Table 4 shows the fractions of exenatide or sodium caprate released from the tablets coated with enteric polymer, ethyl cellulose, and HPMC containing 50 mg sodium caprate. The results are also summarized in FIG. 2B. As in the previous experiment, the release of exenatide and sodium caprate is substantially synchronous. Notably, release from the ethyl cellulose coated tablets is further extended compared to the tablets containing a cellulose acetate layer (maximum release reached at 5 hrs vs. 3 hrs).
• Table 4 Release of exenatide and sodium caprate from HPMC, enteric and ethyl cellulose (EC) coated tablets.
• Table 7 Treatment groups for evaluating the effect of a bioadhesive layer on the bioavailability of exenatide.
• Example 3 As in Example 3, the results indicate that absorption of exenatide is significantly affected by the bioadhesive layer. Without a bioadhesive layer, exenatide absorption is moderate in the presence of 500 mg sodium caprate as permeation enhancer. The coating with AA1 significantly improves exenatide absorption.
• Table 10 Effect of sodium caprate amount on the bioavailability of exenatide in the presence of AA1 and enteric layer.
• Table 11 Treatment groups for evaluating the effect of a unidirectional release layer on the bioavailability of exenatide.
• Table 14 Bioavailability of oral exenatide in the presence of 100 mg sodium caprate, HPMC, ethyl cellulose and enteric coating.
• the core tablets were fabricated according to the formula listed in Table 15 by compression using a single tablet press. All the components except exenatide and magnesium stearate were first weighed and mixed thoroughly. Granules were then formed with 15% polyvinylpyrrolidone (PVP) in 25% ethanol as adhesive material and dried under vacuum overnight. The granules were sieved through a 22-mesh screen and weighed based on the single tablet along with exenatide and magnesium stearate. The composition was mixed and pressed into tablets. All tablets were weighed individually, and those tablets with more than 5% deviation from the mean tablet weight were excluded from further experiments.
• PVP polyvinylpyrrolidone
• Table 15 Core tablet formulation (amounts shown in milligrams).
• the core tablets were coated with hydroxypropyl methylcellulose (HPMC) with or without enteric material EUDRAGIT® L30D-55.
• HPMC hydroxypropyl methylcellulose
• EUDRAGIT® L30D-55 enteric material EUDRAGIT® L30D-55
• an aqueous solution of 6% HPMC and 1.5% polyethylene glycol, MW 6000 (PEG 6000) was used in a tablet pan coater (BY300A, Yellow Sea Machinery).
• the weight gain due to the bioadhesive layer was 3-4 mg.
• For coating with L30D-55 an aqueous solution of 3% HPMC and 0.6% L30D-55 was used in the tablet pan coater.
• the coated tablets were dried at 40°C for about 14 hrs.
• the weight gain due to the bioadhesive layer was 3 mg.
• the tablets coated with a bioadhesive layer were subsequently coated with a semi-permeable cellulose acetate layer.
• the tablets were first covered on one side with adhesive paper to create unidirectional release openings.
• the tablets were coated in a pan coater with a unidirectional coating solution containing 3% cellulose acetate and 1.2% polyethylene glycol, MW 2000 (PEG 2000) in a mixture of acetone and formic acid (9: 1 v/v) and dried at 40°C overnight.
• the weight gain due to the unidirectional release layer was 2 mg.
• the adhesive paper was peeled off to expose the unidirectional release openings.
• the tablets coated with a bioadhesive HPMC layer without L30D-55 were further coated with an enteric layer.
• the coating mixture contained 200 g L30D-55, 12 g ultrafine talc powder, and 6 g polyethylene glycol, MW 6000 (PEG 6000), homogenized in water to a final volume of 400 ml.
• the coating was performed in a small scale pan coater, and the tablets were dried at 40°C for 14 hrs.
• the weight gain due to the enteric layer was 25 mg.
• Table 16 Treatment groups for evaluating absorption of oral exenatide in dogs.
• Calcium phosphate insulin particles were prepared and used as drug carrier in this study. Insulin (5 mg/ml) was dissolved in 40 ml solution A containing 20 mM sodium dibasic phosphate, 20 mM HEPES buffer at pH 6.9, 2% PEG (molecular weight 6000), and 0.5% ursodeoxycholate (UDCA). UDCA was dissolved in 1.5 ml ethanol before addition. Equal volume (40 ml) solution B containing 0.0 IN HC1 and 60 mM CaCl 2 was mixed with solution to induce precipitation. The particles were centrifuged at 15000 rpm for 30 min and recovered particles were dried completely under vacuum.
• the insulin content in the particles was measured by suspending the particles at 0.2 mg/ml in 50 mM sodium phosphate buffer at pH 9.1 at 37°C for 15 min. Insulin was estimated by reverse phase high-performance liquid chromatography (RP-HPLC) using a known amount insulin as standard. Insulin content in this particular batch of calcium phosphate particles was 0.56 mg/mg and insulin recovery was 99%.
• RP-HPLC reverse phase high-performance liquid chromatography
• the core tablets were fabricated according to the formula listed in Table 16 by compression with a single tablet press. All the components except insulin, silica powder and magnesium stearate were first weighed and mixed thoroughly. Granules were then formed with 8% polyvinylpyrrolidone (PVP) in 25% ethanol as adhesive material and dried under vacuum overnight. The granules were sieved through a 22-mesh screen and weighed based on the single tablet along with insulin, silica powder and magnesium stearate. The composition was mixed and pressed into tablets. All tablets were weighed, and those tablets with more than 5% deviation from the mean tablet weight were excluded from further experiments. Tablet hardness, thickness and friability were also monitored.
• PVP polyvinylpyrrolidone
• Table 16 Core tablet formulation (amounts shown in milligrams).
• the core tablets were coated with hydroxypropyl methylcellulose (HPMC E50) and enteric material EUDRAGIT® L30D-55.
• HPMC E50 hydroxypropyl methylcellulose
• EUDRAGIT® L30D-55 enteric material EUDRAGIT® L30D-55.
• An aqueous suspension of 3% HPMC and 0.6% L30D-55 was used in the tablet pan coater (BY300A, Yellow Sea Machinery).
• the coated tablets were dried at 40°C for about 14 hrs.
• the weight gain due to the bioadhesive layer was 3 mg. 9.4 Unidirectional Release Layer
• the tablets coated with a bioadhesive layer were subsequently coated with a semi -permeable cellulose acetate layer.
• the tablets with diameter of 9 mm were first covered on one side with adhesive paper having circular shape of 7 mm diameter.
• the tablets were coated in a pan coater with a unidirectional coating solution containing 3% cellulose acetate and 1.2% polyethylene glycol, MW 2000 (PEG 2000) in a mixture of acetone and formic acid (9: 1 v/v) and dried at 40°C overnight.
• the weight gain due to the unidirectional release layer was 2 mg.
• the circular sticker was peeled off to expose the unidirectional release opening.
• Insulin release was evaluated first in 100 ml 0.01N HC1 for 2 hrs in a dissolution apparatus with a basket design at 100 rpm agitation and 37°C. Aliquots were taken at 1 hr and 2 hrs and insulin content was measured by RP-HPLC. The tablets were then transferred into 100 ml of simulated intestinal fluid (SIF) at pH 6.8 under same conditions, and aliquots were subject to RP-HPLC at various time points to measure insulin content.
• SIF simulated intestinal fluid
• the insulin release profile is shown in FIG. 8A.
• the tablets were stable in the acid solution, as evidenced by the observation that less than 10% of insulin was released at 2 hr incubation. Insulin release in SIF was gradual and completed in about 3-4 hrs.
• Table 17 Treatment groups for oral insulin administration in somatostatin infused dogs.
• Blood glucose concentration was measured with a glucometer and matching testing strips (Johnson & Johnson, OneTouch ® ), and serum samples of 0.5-0.6 ml were recovered after blood samples were collected and centrifuged at 3000 rpm for 10 min. The samples were frozen at -20 °C, and insulin concentration was measured by ELISA (Linco).
• the core tablets were fabricated according to the formula listed in Table 18 by compression with a single tablet press. All the components except insulin, silica powder and magnesium stearate were first weighed and mixed thoroughly. Granules were then formed with 8% polyvinylpyrrolidone (PVP) in 25% ethanol as adhesive material and dried under vacuum overnight. The granules were sieved through a 22-mesh screen and the amount needed for each tablet was weighed individually and followed by addition of insulin, silica powder and magnesium stearate. The composition was mixed and pressed into tablets. Hardness, friability, and thickness of the tablets were also measured.
• PVP polyvinylpyrrolidone
• Table 18 Core tablet formulation (amounts shown in milligrams).
• the core tablets were coated with hydroxypropyl methylcellulose (HPMC) with or without enteric material EUDRAGIT® L30D-55.
• HPMC hydroxypropyl methylcellulose
• EUDRAGIT® L30D-55 enteric material EUDRAGIT® L30D-55
• an aqueous solution of 6% HPMC and 1.5% polyethylene glycol, MW 6000 (PEG 6000) was used in a tablet pan coater (BY300A, Yellow Sea Machinery).
• the weight gain due to the bioadhesive layer was 3-4 mg.
• For coating with L30D-55 an aqueous solution of 3% HPMC and 0.6% L30D-55 was used in the tablet pan coater.
• the coated tablets were dried at 40°C for about 14 hrs.
• the weight gain due to the bioadhesive layer was 3 mg.
• the tablets coated with a bioadhesive layer were subsequently coated with a semi-permeable cellulose acetate layer.
• the 10 mm diameter tablets were first covered on one side with circular stickers of 7 mm diameter.
• the tablets were coated in a pan coater with a unidirectional coating solution containing 3% cellulose acetate and 1.2% polyethylene glycol, MW 2000 (PEG 2000) in a mixture of acetone and formic acid (9: 1 v/v).
• the tablets were dried at 40°C overnight after coating was completed.
• the weight gain due to the unidirectional release layer was 2 mg.
• the adhesive paper was peeled off to expose the unidirectional release openings.
• the tablets coated with a bioadhesive HPMC layer without L30D-55 were further coated with an enteric layer.
• the coating mixture contained 200 g L30D-55, 12 g ultrafine talc powder, and 6 g polyethylene glycol, MW 6000 (PEG 6000), homogenized in water to a final volume of 400 ml.
• the coating was performed in a small scale pan coater, and the tablets were dried at 40°C for 14 hrs.
• the weight gain due to the enteric layer was 25 mg.
• Table 19 Treatment groups for oral insulin formulation.
• the oral insulin tablet administration induced a significant blood glucose reduction, similar to insulin injection, whereas blood glucose in blank treated animals showed an initial decrease followed by rapid increase.
• the blood glucose decrease was first observed at 1 hr after tablet administration, while the same effect was only seen at 4 hr after the enteric coated tablet administration.
• Formulations of insulin and exenatide listed in Table 20 were produced by direct compression. Insulin and exenatide powders were sieved through a 200-mesh screen and mixed thoroughly with all the excipients. The compositions were compressed into tablets using a rotary press. Hardness, friability, and thickness of the tablets were also measured.
• Table 20 Core tablet formulation (amounts shown in milligrams).
• silica - silica powder silica - silica powder.
• Blend uniformities of insulin and exenatide were evaluated according to U.S. Pharmacopeia General Chapter ⁇ 905>, "Uniformity of Dosage Units" ("USP ⁇ 905>”), and samples of the same weight (equal to that of a tablet) were collected from different locations after the blends were mixed completely. Insulin or exenatide content was measured by RP- HPLC. The blend uniformity results are shown in the Table 21.
• Insulin and exenatide powders were sieved through a 200-mesh screen and suspended in 8% PVP in ethanol. The drug suspensions were sonicated lightly until no visible large particles were detected. All other excipients except silica powder and magnesium stearate were weighed and pre-mixed thoroughly in a granulator. The drug suspensions were added to the excipient blends to form granules, which then were sieved through a 18-mesh screen and dried under vacuum. After drying and addition of silica powder and magnesium stearate, the compositions were compressed into tablets using a rotary press. Hardness, friability, and thickness of the tablets were also measured. Table 22: Core tablet formulation for insulin at 1 mg (amounts shown in milligrams; Lot 181).
• Table 23 Core tablet formulation for insulin at 0.8 mg (amounts shown in milligrams; Lot 182).
• Table 24 Core tablet formulation for exenatide at 0.6 mg (amounts shown in milligrams; Lot 178-1).
• Table 25 Core tablet formulation for exenatide at 0.4 mg (amounts shown in milligrams; Lot 183).
• Table 26 Core tablet formulation for exenatide at 0.4 mg (amounts shown in milligrams; Lot 184).
• Insulin or exenatide content in these tablets are measured by RP-HPLC and content uniformity is evaluated according to USP ⁇ 905>. The results are shown in Table 27.
• Table 27 Insulin and exenatide content uniformity in Lots 178-184.
• Example 13 Stability of Exenatide in Different Formulation & Processes
• Table 29 Basic core tablet formulation (amounts shown in milligrams).
• tablets fabricated by direct compression or non-solvent granulation show good stability at these conditions, similar to exenatide powder. It is notable that addition of low molecular weight PEG caused instability even in formulations produced by the non-solvent granulation process, which may be attributed to partial solubility of exenatide in low molecular weight PEG.
• the core tablets were fabricated according to the formula listed in Table 30 by non-solvent granulation followed by compression with a rotary press. All the components except insulin, PVP, silica powder, and magnesium stearate were first weighed and mixed thoroughly in a granulator. Insulin powder was suspended in 8% polyvinylpyrrolidone (PVP) in ethanol and sonicated to breakdown the large insulin particles. Granules were formed by adding the insulin suspension to the other components and drying the mixture under vacuum overnight. Silica powder and magnesium stearate were added to the dried granules and the composition was mixed and pressed into tablets. Hardness, friability, and thickness of the tablets were also measured.
• PVP polyvinylpyrrolidone
• Table 30 Core tablet formulation (amounts shown in milligrams).
• the core tablets were coated with hydroxypropyl methylcellulose (HPMC) with 6% HPMC and 1.5% polyethylene glycol (MW 6000) solution in a tablet pan coater (BY300A, Yellow Sea Machinery).
• HPMC hydroxypropyl methylcellulose
• MW 6000 polyethylene glycol
• the tablets coated with the bioadhesive layer were subsequently coated with a semi-permeable ethyl cellulose layer.
• the 10 mm diameter tablets were first covered on one side with circular stickers of 7 mm diameter.
• the tablets were coated in a pan coater with a unidirectional coating solution containing 3% ethyl cellulose and 1.2% polyethylene glycol (MW 2000) in ethanol.
• the tablets were dried at room temperature after coating was completed.
• the weight gain due to the unidirectional release layer was 2 mg.
• the adhesive paper was peeled off to expose the unidirectional release openings.
• the tablets were further coated with an enteric layer.
• the coating mixture contained 8% L30D-55, 2% polyethylene glycol (MW 6000) in ethanol.
• the coating was performed in a small scale pan coater and the weight gain due to the enteric layer was 20 mg.
• oral insulin tablets induced significant blood glucose reduction within 2 to 3 hours after administration, similar to insulin injection, whereas blood glucose in blank treated animals was relatively steady.
• the blood glucose is often controlled within a tight range in normal subjects. Therefore, the glucose reduction even in sc injection was transit. Oral insulin tablet induced glucose reduction in similar magnitude and transit fashion as injected insulin in normal beagles.
• the core tablets were fabricated according to the formula listed in Table 32 by compression with a rotary press. All the components except exenatide, silica powder and magnesium stearate were first weighed and mixed thoroughly. Granules were then formed with exenatide dissolved in 8% polyvinylpyrrolidone (PVP) in 25% ethanol as adhesive material, and the granules were dried under vacuum overnight, sieved through a 22-mesh screen, and silica powder and magnesium stearate were added. The composition was mixed and pressed into tablets. Tablet weight, hardness, thickness and friability were monitored.
• PVP polyvinylpyrrolidone
• Table 32 Core tablet formulation (amounts shown in milligrams).
• the core tablets were coated with hydroxypropyl methylcellulose (HPMC E50) and enteric material EUDRAGIT® L30D-55 using an aqueous suspension of 3% HPMC and 0.6% L30D-55 in a pan coater (BY300A, Yellow Sea Machinery).
• HPMC E50 hydroxypropyl methylcellulose
• EUDRAGIT® L30D-55 enteric material EUDRAGIT® L30D-55 using an aqueous suspension of 3% HPMC and 0.6% L30D-55 in a pan coater (BY300A, Yellow Sea Machinery).
• the coated tablets were dried at 40°C for about 14 hrs.
• the weight gain due to the bioadhesive layer was 3 mg.
• the above tablets were further coated with a semi-permeable cellulose acetate layer.
• 9 mm tablets were first covered on one side with circles of adhesive paper of 7 mm diameter, followed by coating with a solution containing 3% cellulose acetate and 1.2% polyethylene glycol, MW 2000 (PEG 2000) in a mixture of acetone and formic acid (9: 1 v/v) in a pan coater.
• the circular stickers were peeled off to expose the unidirectional release openings after coating and drying were completed.
• the tablets were not covered with stickers and coated with the same cellulose acetate solution.
• the coated tablets were dried at 40°C overnight.
• the completed tablets were ablated with a laser drilling equipment (CMS) to form a 7 mm diameter aperture similar to the one obtained by the manual process described above.
• CMS laser drilling equipment
• Table 34 Treatment groups for oral exenatide.
• the core tablets were fabricated according to the formula listed in Table 34 by compression with a single tablet press. All the components except insulin, silica powder and magnesium stearate were first weighed and mixed thoroughly. Granules were then formed with 8% polyvinylpyrrolidone (PVP) in 25% ethanol as adhesive material and dried under vacuum overnight. The granules were sieved through a 22-mesh screen, and the amount needed for each tablet was weighed individually, followed by the addition of insulin, silica powder and magnesium stearate. The composition was mixed and pressed into tablets. Hardness, friability, and thickness of the tablets were also measured.
• PVP polyvinylpyrrolidone
• Table 34 Core tablet formulation (amounts shown in milligrams).
• the core tablets were coated with an aqueous suspension of 3% HPMC and 0.6% L30D-55 in a tablet pan coater.
• the coated tablets were dried at 40°C for 14 hrs.
• the weight gain due to the bioadhesive layer was 3 mg. 16.3 Unidirectional Release Layer
• the tablets coated with the bioadhesive layer were subsequently coated with a semi-permeable cellulose acetate layer.
• the 10 mm diameter tablets were first covered on one side with circular sticker of 7 mm diameter.
• the tablets were coated in a pan coater with a unidirectional coating solution containing 3% cellulose acetate and 1.2% polyethylene glycol, MW 2000 (PEG 2000) in a mixture of acetone and formic acid (9: 1 v/v).
• the tablets were dried at 40°C overnight after coating completed.
• the weight gain due to the unidirectional release layer was 2 mg.
• the adhesive paper was peeled off to expose the unidirectional release openings.
• Table 35 Treatment groups for oral insulin formulation.
• FIG. 13 Blood samples were collected and blood glucose concentration was measured with a glucometer. The effects of two oral insulin formulations on blood glucose are shown in FIG. 13. [0240] As shown in FIG. 13, oral insulin tablets induced a significant blood glucose reduction, similar to insulin injection. The glucose reduction was dose-dependent when the response in 25U oral insulin was compared to either 50U oral insulin or 25U x 2 treatment. The glucose reduction appeared to be approximately equivalent in the 50U and 25U x 2 oral insulin treated groups.
• Exenatide tablets were fabricated using the ethanol granulation process as described earlier. The formulation for this batch of tablets is listed in Table 36. Exenatide power was suspended in 8% PVP in ethanol and sonicated lightly until no visible large particles detected. All other excipients except silica powder and magnesium stearate were weighed and pre-mixed thoroughly in a granulator. The drug suspension was added to the excipient blend to form granules, which were then sieved through 18-mesh screen and dried under vacuum. After the addition of silica powder and magnesium stearate, the composition was compressed into tablets on a rotary press. Hardness, friability, and thickness of the tablets were also measured.
• Table 36 Core tablet formulation (amounts shown in milligrams; Lot 184).
• the core tablets were coated with an aqueous suspension of 3% HPMC and 0.6% L30D-55 in 50% ethanol in a tablet pan coater. Alternatively, the core tablets were coated with 2.6% HPMC, 0.8% L30-D55, and 0.6% PEG in 50% ethanol. The coated tablets were dried at 40°C for 14 hrs. The weight gain due to the bioadhesive layer was 3-4 mg. 17.3 Unidirectional Release Layer
• the tablets coated with the bioadhesive layer were subsequently coated with a semi-permeable ethyl cellulose in a pan coater with a unidirectional coating solution containing 3.2% ethyl cellulose, 0.6% polyethylene glycol, MW 2000 and 0.2% triacetin in 85%o ethanol.
• the tablets were dried at 40°C overnight after coating was completed.
• the weight gain due to the unidirectional release layer was 2 mg.
• One side of the tablets was ablated with a laser to form a unidirectional release opening of 7 mm in diameter on these 9 mm diameter tablets.
• Table 37 Treatment groups for oral insulin formulation.

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