WO2006103657A2 - Composition solide de distribution intra-buccale d'insuline - Google Patents

Composition solide de distribution intra-buccale d'insuline Download PDF

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Publication number
WO2006103657A2
WO2006103657A2 PCT/IL2006/000381 IL2006000381W WO2006103657A2 WO 2006103657 A2 WO2006103657 A2 WO 2006103657A2 IL 2006000381 W IL2006000381 W IL 2006000381W WO 2006103657 A2 WO2006103657 A2 WO 2006103657A2
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WO
WIPO (PCT)
Prior art keywords
insulin
gum
solid composition
phospholipid
hydrophilic polymer
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PCT/IL2006/000381
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English (en)
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WO2006103657A3 (fr
Inventor
Adel Pinhasi
Mila Gomberg
Original Assignee
Dexcel Pharma Technologies Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from IL174387A external-priority patent/IL174387A0/en
Application filed by Dexcel Pharma Technologies Ltd. filed Critical Dexcel Pharma Technologies Ltd.
Priority to US11/887,653 priority Critical patent/US20090274758A1/en
Publication of WO2006103657A2 publication Critical patent/WO2006103657A2/fr
Publication of WO2006103657A3 publication Critical patent/WO2006103657A3/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • the present invention relates to a solid composition for intra-oral delivery of insulin, and to a drug delivery system.
  • intra-oral as used herein is intended to include delivery to the oral cavity, buccal, lingual and sublingual areas
  • the invention is based on a new delivery system consisting of a mixture of a hydrophilic (water soluble, swellable) polymer, carefully chosen lipids, insulin, and optionally surfactant, preservative, antioxidant, stabilizers, flavors and sweeteners.
  • the delivery system is preferably a bioadhesive system which is adhered to a soft tissue in the buccal, sublingual or other oral cavity areas to release insulin locally to be absorbed by mucosa for systemic absorption.
  • the hydration occurs, upon exposing the system to the oral cavity liquid, which hydration is responsible for adhesion. Hydration of the system may simultaneously result in dissolution of the polymer and spontaneous arrangement of the lipid component into bilayer liposomes (vesicles), and/or micelles, lamellar structures (single or multilamellar) and/or emulsion structure and or any other liquid crystalline structures in situ. In this manner the insulin dose or a part of it, can be entrapped into the liposomes (vesicles) or other lipid arrangements. The absorption of insulin into the blood system can thereby mainly occur through intra-oral mucosa. A high oral bioavailability of insulin (more than 10%)using such a device is achieved. BACKGROUND OF THE INVENTION
  • a well-known problem with the administration of insulin is that it is susceptible to enzymatic degradation when administrated orally. For this reason, parenteral administration has been the most widely used method.
  • administration by injection is both inconvenient and unpleasant for the patient, particularly because of the fact that injections must be repeated regularly over protracted periods.
  • noninjectable (nonparenteral) formulations of insulin have been studied.
  • the oral cavity is the first site that an orally delivered drug encounters. It is characterized by a pH that is nearly neutral (6 to 7.5) and a relatively small surface area for drug absorption.
  • the sublingual mucosa are endowed with a large blood flow and therefore offer an opportunity for drug absorption as do the buccal membranes ( the gums).
  • the residence time of a delivery system in the oral cavity is usually short, several seconds for a tablet that is being swallowed to several minutes for a lozenge that is being sucked.
  • Small tablets can be held under the tongue for short periods of time to allow immediate drug delivery (e.g. Nitroglycerine tablets for vasodialation).
  • Current research for delivery of systemic drugs through the oral cavity is mainly concerned with buccal delivery.
  • Polymeric adhesives are used to affix the tablet to the gums through which the drug can diffuse over several hours.
  • Targeting drugs for local treatment of oral cavity symptoms can be achieved by similar means.
  • Films can also be used to deliver drugs to the oral cavity as will be described later.
  • Buccal delivery of peptides and proteins has potential advantages over other available routes. It avoids degradation by gastrointestinal enzymes and first- pass hepatic metabolism. Buccal delivery has high patient compliance and excellent accessibility, and self-placement of a dosage form is possible. Because of the natural function (i.e. to line and protect the inner surface of the cheek) of the buccal mucosa, it is less sensitive to irritation and damage than the other absorptive mucosa. Furthermore, there are fewer proteolytic enzymes at work as compared with oral administration to the gastrointestinal tract and in addition, the buccal mucosa is highly vascularized.
  • a novel method and formulation for spontaneous arrangement of any lipid- based structures such as liposomes (vesicles), micelles, lamellar structures (single or multilamellar), emulsions and any other liquid crystalline structures.
  • lipid- based structures such as liposomes (vesicles), micelles, lamellar structures (single or multilamellar), emulsions and any other liquid crystalline structures.
  • liposomes Formation of liposomes is enabled by addition of excess water.
  • the loading of active ingredients is carried out by the addition of a low amount solution of the active ingredient into the proliposome mixture followed by a further addition of water enabling the formation of the liposomes. It was reported that by this manner generally oligo-or multilamellar vesicles with a void volume of at least 2 ml per gram of lipid, and capable of achieving a drug entrapment ratio of more than 20% can be obtained (European Patent 0158441).
  • a solid composition for intra-oral delivery of insulin comprising insulin; a hydrophilic polymer matrix; and a phospholipid providing insulin bioavailability of at least 5%.
  • a solid composition for intra-oral delivery of insulin comprising insulin; a hydrophilic polymer matrix; and a phospholipid, providing insulin bioavailability of at least 10%.
  • a solid composition for intra-oral delivery of insulin comprising insulin; a hydrophilic polymer matrix; and a phospholipid, providing insulin bioavailability of at least 15%.
  • a solid composition for intra-oral delivery of insulin comprising insulin; a hydrophilic polymer matrix; and a phospholipid, providing insulin bioavailability of at least 20%.
  • a solid composition for intra-oral delivery of insulin comprising insulin; a hydrophilic polymer matrix; and a liposome forming agent, wherein the composition achieves a bioavailability of insulin of at least 5%.
  • a solid composition for intra-oral delivery of insulin comprising insulin; a hydrophilic polymer matrix; and a liposome forming agent, wherein the composition achieves a bioavailability of insulin of at least 10%.
  • a solid composition for intra-oral administration of insulin comprising Insulin, a hydrophilic polymer matrix, and a phospholipid; wherein upon contact with the oral cavity liquid, said composition forms in-situ particles selected from the group consisting of micelles, emulsions, liposomes, or mixed structures thereof.
  • the present invention provides a solid composition for intra-oral delivery of insulin, comprising insulin, a hydrophilic polymer matrix and a phospholipid; wherein upon contact with the oral cavity liquid, said composition forms in-situ particles that enhance the absorption of insulin selected from the group consisting of: micelles, emulsions, liposomes and/or mixed structures thereof.
  • the solid compositions according to the present invention are adapted for absorption of insulin via buccal mucosa, lingual mucosa and/or sublingual mucosa.
  • the present invention preferably provides a solid composition as defined adapted for intra-oral absorption of insulin via buccal mucosa, lingual mucosa and/or sublingual mucosa.
  • the formulation comprises at least one hydrophilic polymer.
  • the hydrophilic polymer is water-soluble polymer which is selected from the group consisting of a Povidone (PVP: polyvinyl pyrrolidone), polyvinyl alcohol, copolymer of PVP and polyvinyl acetate, HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), carboxymethyl cellulose, hydroxyethyl cellulose, hydroxylmethyl cellulose, methylcellulose, gelatin, proteins, collagen, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, starch, a water soluble synthetic polymer, polyacrylic acid, polyhydroxyethylmethacrylate (PHEMA), polyacrylamid, polymethacrylates and their copolymers, gum, water soluble gum, polysaccharide, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate,
  • PVP polyvinyl pyrrolidon
  • gums include, for example and without limitation, heteropolysaccharides such as xanthan gum(s), homopolysaccharides such as locust bean gum, galactans, mannans, vegetable gums such as alginates, gum karaya, pectin, agar, tragacanth, accacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide gums (e.g. hydrocolloids), and mixtures of any of the foregoing.
  • heteropolysaccharides such as xanthan gum(s), homopolysaccharides such as locust bean gum, galactans, mannans, vegetable gums such as alginates, gum karaya, pectin, agar, tragacanth, accacia, carrageenan, tragacanth, chitosan, agar, alginic acid, other polysaccharide gums (
  • the hydrophilic polymer may be water insoluble but water swellable polymer.
  • the swellable polymer may be more preferably selected from the groups consisting of a water insoluble cross-linked polysaccharide, a water insoluble polysaccharide, a water insoluble synthetic polymer, a water insoluble cross-linked protein, a water insoluble cross- linked peptide, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen, water insoluble cross linked polyacrylic acid, water insoluble cross-linked cellulose derivatives, water insoluble cross-linked polyvinyl pyrrolidone, micro crystalline cellulose, insoluble starch, micro crystalline starch and a combination thereof.
  • the water insoluble cross-linked polysaccharide is preferably, selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xantham gum, guar gum, tragacanth gum, locust bean gum, carrageenan, and metal salts thereof, and covalently cross-linked derivatives thereof.
  • the modified cellulose is preferably, selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxymethyl cellulose, carboxymethylcellulose, and metal salts of carboxymethylcellulose.
  • the hydrophilic polymer may be a polymeric blend consisting of a combination of at list a water soluble polymer and at least a water insoluble but swellable polymer.
  • the formulation comprises at least one liposome forming agent.
  • the liposome forming agent is selected from the group consisting of egg phosphatidylcholine (PC), dilauryl phosphatidylcholine (DLPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), dioleoyl phosphatidylcholine (DOPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol(DPPG), dimyristoyl phosphatide acid (DM PA), dipalmitoyl phosphatide acid (DPPA), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidylcholine (DSPC), brain phosphatidylserine (PS), brain sphingomyelin (SM), cholesterol(C), cardiolipin (CL), trioct
  • PC
  • the formulation contains at least one absorption enhancer, especially absorption enhancers selected from the group consisting of Na-salicylate-chenodeoxy cholate, Na deoxycholate, polyoxyethylene 9-lauryl ether, chenodeoxy cholate-deoxycholate and polyoxyethylene 9-lauryl ether, monoolein, Natauro-24,25-dihydrofusidate,Na-taurodeoxycholate,Na-glycochenodeoxycholate, oleic acid, linoleic acid, linolenic acid, polyoxyethylene ethers, polyoxyethylene sorbitan esters, polyoxyethylene 10-lauryl ether, polyoxyethylene 16-lauryl ether, azone(1-dodecylazacycloheptane-2-one), and sodium chloride, sodium bicarbonate in combination with the above mentioned materials.
  • absorption enhancers selected from the group consisting of Na-salicylate-chenodeoxy cholate
  • the formulation may further comprise an antioxidant.
  • the antioxidant is selected from the group consisting of 4,4 (2,3 dimethyl tetramethylene dipyrochatechol), Tocopherol- rich extract (natural vitamin E), ⁇ -tocopherol (synthetic Vitamin E), ⁇ - tocopherol, ⁇ tocopherol, ⁇ -tocopherol, Butylhydroxinon, Butyl hydroxyanisole (BHA), Butyl hydroxytoluene (BHT), Propyl Gallate, Octyl gallate, Dodecyl Gallate, Tertiary butylhydroquinone (TBHQ), Fumaric acid, Malic acid, Ascorbic acid (Vitamin C), Sodium ascorbate, Calcium ascorbate, Potassium ascorbate, Ascorbyl palmitate, Ascorbyl stearate, Citric acid, Sodium lactate, Potassium lactate
  • the formulation may further include a chelating agent to increase chelation of trace quantities of metals thereby helping in preventing the loss of the active material by oxidation.
  • a chelating agent to increase chelation of trace quantities of metals thereby helping in preventing the loss of the active material by oxidation.
  • the chelating agent is selected from the group consisting of Antioxidants, Dipotassium edentate, Disodium edentate, Edetate calcium disodium, Edetic acid, Fumaric acid, Malic acid, Maltol, Sodium edentate, Trisodium edetateMost preferably, the chelating agent is citric acid.
  • the formulation may further comprise a synergistic agent (sequestrate).
  • a synergistic agent sequestrate
  • the sequestrate is selected from the group consisting of citric acid and ascorbic acid.
  • chelating agents and sequestrates may optionally be differentiated as follows.
  • a chelating agent such as (preferably) citric acid is intended to help in chelation of trace quantities of metals thereby assisting to prevent the loss of the active ingredient(s), by oxidation.
  • a sequestrate such as (preferably) ascorbic acid, optionally and preferably has several hydroxyl and/or carboxylic acid groups, which can provide a supply of hydrogen for regeneration of the inactivated antioxidant free radical.
  • a sequestrate therefore preferably acts as a supplier of hydrogen for rejuvenation of the primary antioxidant.
  • an antifungal, antimicrobial agent selected from the group consisting of ethyl paraben, methyl paraben, propyl paraben, metacrezole and combinations thereof may also be added to the composition.
  • the formualtion may also include additional excipients such as lubricants, bioadhesive agents, plasticizers, antisticking agents, natural and synthetic flavorings and natural and synthetic colorants.
  • the formulation according to the present invention further contains at least one of a wetting agent, suspending agent, surfactant, and dispersing agent, or a combination thereof.
  • suitable wetting agents include, but are not limited to, poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, docusate sodium.
  • suspending agents include but are not limited to, alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxyethylcellulose, hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, medium chain triglycerides, methylcellulose, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyvinyl pyrrolidone (PVP), propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, and tragacanth.
  • surfactants include but are not limited to, anionic surfactants such as docusate sodium and sodium lauryl sulfate; cationic, such as cetrimide; nonionic, such as polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.
  • Suitable dispersing agents include but are not limited to, poloxamer, polyoxyethylene sorbitan fatty acid esters (polysorbates) and sorbitan fatty acid esters.
  • the content of the wetting agent, surfactant, dispersing agent and suspending agent may optionally be in an amount of from about 0 to about 30% of the weight of the dry film of the formulation.
  • the formulation according to the present invention may also optionally feature a buffering agent, which is preferably selected from the group consisting of an inorganic salt compound and an organic alkaline salt compound. More preferably, the buffering agent is selected from the group consisting of potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium citrate, sodium hydroxide, calcium carbonate, dibasic sodium phosphate, monosodium glutamate, tribasic calcium phosphate, monoethanolamine, diethanolamine, triethanolamine, citric acid monohydrate, lactic acid, propionic acid, tartaric acid, fumaric acid, malic acid, and monobasic sodium phosphate.
  • a buffering agent is selected from the group consisting of potassium bicarbonate, potassium citrate, potassium hydroxide, sodium bicarbonate, sodium citrate, sodium hydroxide, calcium carbonate, dibasic sodium phosphate, monosodium glutamate, tribasic calcium phosphate, monoethanolamine, diethanolamine, triethanolamine, citric acid monohydrate
  • a solid composition for intra-oral delivery comprising a pharmaceutically acceptable active agent; a hydrophilic polymer matrix; and a phospholipid, wherein the composition provides bioavailability of said pharmaceutically acceptable active agent of at least about 5% and said pharmaceutically acceptable active agent has a dissolution rate higher than that of the said hydrophilic polymer.
  • a solid composition for intra-oral delivery of insulin comprising insulin, a hydrophilic polymer matrix and a phospholipid providing a reduction of blood glucose levels of a subject by at least 5%.
  • the invention also provides a solid composition comprising a hydrophilic polymer matrix, at least one phospholipid and insulin.
  • a solid composition comprising a hydrophilic polymer matrix, lecithin and insulin providing the reduction of glucose blood level of a subject by at least about 5%.
  • the present invention also provides a solid composition comprising a hydrophilic polymer matrix, phosphatidylcholine and insulin providing the reduction of glucose blood level of a subject by at least about 5%.
  • Also provided according to the present invention is a solid composition as defined herein that provides a reduction of blood glucose levels of a subject by at least about 5%.
  • a method for the reduction of the blood glucose plasma levels of a subject by at least 5% comprising administering to said subject a solid composition comprising: insulin, a hydrophilic polymer matrix and a phospholipid.
  • the present invention also provides a method for treating Type I diabetes comprising the intra-oral use of a solid composition comprising: insulin, a hydrophilic polymer matrix and a phospholipid.
  • Also provided according to the present invention is a method for decreasing the need for at least one subcutaneous injection a day for Type I diabetes patients comprising the intra-oral use of a solid composition comprising: insulin, a hydrophilic polymer matrix and a phospholipid.
  • a method for treating Type Il diabetes comprising the intra-oral use of a solid composition comprising: insulin, a hydrophilic polymer matrix and a phospholipid.
  • the present invention also provides a method for decreasing the need for at least one subcutaneous injection a day for Type Il diabetes patients comprising the intra-oral use of a solid composition comprising: insulin, a hydrophilic polymer matrix and a phospholipid.
  • a drug delivery system comprising a solid composition, said composition comprising a hydrophilic, blended, single phase polymeric material having insulin and a phospholipid incorporated therein for oral transmucosal delivery of said insulin via intra-oral mucosa.
  • said phospholipid is preferably selected from the group consisting of lecithin or phosphotidyl-cholin.
  • said material is a bioadhesive film.
  • a drug delivery system comprising a hydrophilic bioadhesive blended single phase polymeric material having insulin and lecithin or phosphatidyl-cholin incorporated therein for oral transmucosal delivery of said insulin via intra-oral mucosa, wherein upon contact with saliva, said system forms in situ particles selected from the group consisting of micelles, emulsions and liposomes, incorporating said insulin, for enhancing the absorption thereof.
  • a drug delivery system as defined, adapted for oral transmucosal delivery via mucosa selected from the group consisting of buccal mucosa, lingual mucosa, and sublingual mucosa any other places relating to oral cavity.
  • the drug delivery system provides an oral viability of at least 5%.
  • a drug delivery system comprising a hydrophilic bioadhesive blended single phase polymeric material having insulin and phospholipids incorporated therein for oral transmucosal delivery of said insulin via intra-oral mucosa wherein upon contact with saliva, said system forms in situ particles selected from the group consisting of micelles, emulsions and liposomes, incorporating said insulin, for enhancing the absorption thereof.
  • the present invention suggests a novel system for intra-oral (oral cavity) delivery of insulin utilizing a spontaneous formation of liposomes by the components constituting the system.
  • the system is based on the unique combination of a hydrophilic water soluble polymer and a proper lipid.
  • the principle of the system according to the present invention is based on the fact that exposure of the hydrophobic moieties of amphiphils to water or aqueous solutions is thermodynamically unfavorable. Protection of these portions from aqueous solutions is possible through self-aggregation of the amphiphils where the hydrophobic moieties have minimal contact with water molecules.
  • phospholipids spontaneously self-aggregate to form globular structures i.e. liposomes and/or micelles.
  • the present invention exploits the unique combination of a carefully chosen lipid and a water soluble polymeric matrix. Spontaneous formation of liposomes and/or micelles is activated by the simple wetting of the mixture where the polymeric matrix starts to be dissolved and consequently the lipid components of the mixture are arranged in the form of bilayers, which eventually enclose to the vesicle structure. Additionally such a system may result in spontaneous formation of micelles, and/or emulsions.
  • This unique mixture can pre-include insulin which is supposed to partially or completely undergo entrapment into the spontaneously formed liposomes and/or micelles.
  • This system has a number of important advantages over existing methods for preparation of liposomes and/or micelles being used for pharmaceutical applications.
  • the main advantage of the system is the avoidance of use of unacceptable solvents that could give rise to undesirable toxic solvent residues.
  • the organic solvents may, in most cases, result in biologically-deactivation of insulin when the active material should pre-entrapped in the lipid film.
  • organic solvents may, in most cases, result in the biological deactivation of the insulin when the active material is pre-entrapped in the lipid film.
  • the system provides a proper solution to the problem of the hydration process of lipids, which is one of the major obstacles in scaling-up for many existing conventional methods of liposome and/or micelle preparation.
  • This unique method is simple and is suitable for scaling-up for production purposes, since it does not require any energy-expensive steps such as evaporation, sonication, freeze drying etc., or other complicated apparatus which can induce limitations to the scale up process.
  • the system according to the present invention can be prepared as a polymeric sheet (film). Thus it will be stable and readily transportable, as well as being suitable for extended storage for subsequent in-situ liposome and/or micelle formation.
  • the liposomes and/or micelles formed spontaneously according to the present invention can readily be loaded in situ with insulin.
  • the loading of liposomes and/or micelles with insulin is out simply, in-situ, during the hydration process of the film, which can take place in situ by saliva or liquids existing in the buccal or oral cavity. Since the liposome formation takes place in-situ, this system also suggests a good solution to the physical stability problem that is a serious problem for almost all conventionally prepared liposomes and/or micelles.
  • US 6290987 B1 discloses a mixed liposome formulation comprising insulin, water, an alkali metal alkyl sulfate, at least one membrane mimetic, and at least one phospholipids.
  • the formulation is applied using an aerosol delivery system for buccal delivery.
  • the patent does not teach, however, any use of a solid polymeric composition for the deliver of insulin nor does it teach the use of self-formation liposomes occurring in situ in the oral cavity.
  • the patent does not teach or suggest a bioadhesive, blended, single-phase polymeric material having insulin incorporated therein.
  • US 6432383 B1 discloses a mixed micellar formulation which includes a micellar proteinic agent, an alkali metal lauryl sulfate, an alkali metal salicylate, an edentate, and at least one absorption enhancing compound.
  • the invention is intended for buccal delivery of insulin.
  • the invention does not, however, disclose a solid polymeric composition for the deliver of insulin nor the delivery system for self-formation micelles or the system providing retention of said micelles in the oral cavity.
  • Claim 1 reads as follows: "An improved oral transmucosal solid dosage form drug delivery formulation comprising: a pharmaceutical agent capable of being absorbed into oral mucosal tissue having a dissolution rate in the solvents found in the oral cavity, a dissolution agent having a dissolution rate in the solvents found in the oral cavity, said dissolution rate of said dissolution agent being greater than said dissolution rate of said pharmaceutical agent, and said pharmaceutical agent being in solid solution with said dissolution agent.”
  • the invention relates to dissolution improvement of the drug molecules which is intended for delivery into the oral cavity where there is relatively little solvent into which a solid dosage form can dissolved.
  • the invention is limited to solid solutions and does not relate to buccal delivery of insulin and also the self-formation of liposomes in situ in the oral cavity.
  • the invention does not provide bioavailability of at least 5% of insulin.
  • WO 00/33817 [PHARES PHARMACEUTICAL RESEARCH N. V] - relates to a carrier for hydrophilic and particularly for hydrophobic compounds that has pharmaceutical and industrial applications. It provides compositions in non-liquid form that are easy to prepare, and that may be solid compacts or may be particulate. At least one solid hydrophilic substance, most preferably a polymer, is typically included in the composition. At least one biologically active compound may be present in the lipid polymer associate. The lipid polymer associates have the potential to swell in water or other aqueous media to form viscous intermediate compositions. Hydration may take place in situ e.g.
  • WO 2004/080438 relates to an orally administrable composition
  • an orally administrable composition comprising at least one physiologically tolerable polymer having, dispersed therein, particles comprising at least one physiologically tolerable lipid and a bioactive agent (that may be hydrophilic), which particles on contact with water or Gl tract liquid form nanometer-sized particles containing said lipid, said bioactive agent and water.
  • the suggested composition according to this invention reveals a phase segregation in the solid phase which can result in a non- homogeneous mixture and thus not capable of forming a homogeneous film and does not teach or suggest a bioadhesive, blended, single-phase polymeric material having insulin incorporated therein.
  • the invention does not disclose a system for buccal delivery of insulin or any ratio of bioavailability of insulin.
  • WO 2004/041118 [UMD, INC.]- discloses a method for topical or systemic delivery of drugs to or through nasal, buccal, vaginal, labial or scrotal epithelium. Said method comprises a step of contacting the vaginal, nasal, buccal, labial or scrotal epithelium with a foam or film composition consisting essentially of a substrate polymer and a pharmacologically effective agent.
  • the invention does not teach the self-formation of liposomes for buccal delivery and absorption of insulin or any ratio of bioavailability of insulin.
  • Figure 1 is the calibration curve of gel permeation chromatography analysis.
  • Figure 2 is the typical electron micrographs (TEM) of negatively stained spontaneously formed liposomes from the wetting of ILFPM.
  • Figure 3 is the typical electron micrographs (TEM) of negatively stained vesicles prepared using the conventional "thin lipid film” method.
  • Figure 4 is the histograms of the size distribution of the liposomes formed from
  • HPC/PC weight ratio of 7:3
  • Figure 5 is the histograms of the size distribution of the liposomes formed from
  • HPC/PC + cholesterol weight ratio of 7:3
  • Figures 6-10 show the results of confocal microscopy analysis of the dissolution and destruction of HPC in the process of spontaneous vesicle formation from the ILFPM.
  • Figures 11 -24 show the results of confocal microscopy analysis of the spontaneous vesicle formation from the ILFPM via transformation of phospholipid to tubular fibril, penetration of water between the bilayers, vesiculation and dispersion of spontaneously formed liposomes processes.
  • Figures 25A and 25B are graphical representations of the effect of PC content in
  • Figure 26 shows the effect of active material content on entrapment and entrapment efficiency.
  • Figures 27A and 27B show the effect of PC+CHL/HPC weight ratio in ILFPM on entrapment and entrapment efficiency.
  • Figure 28 shows the effect of hydrating medium volume on entrapment and entrapment efficiency.
  • the ILFPMs were prepared using a solution casting method. Accordingly, Klucel
  • the Insulin-containing system was prepared using a solution casting method.
  • Insulin solution (3.0 g), containing 100u/ml insulin, m-cresol and glycerol was diluted with purified water (3.6 g).
  • Sodium Lauril Sulphate (0.113 g) was dissolved in the solution, at room temperature using a magnetic stirrer, at about 500 rpm.
  • Ethanol (4.8 g), was added.
  • Klucel L (0.56 g) was dissolved in the solution at room using a magnetic stirrer, at about 500 rpm.
  • Phospolipid (Epikuron 200, 0.24 g) was added to the solution while stirring at room temperature. The solution was then cast into a polyethylene weighing plate and the solvents were allowed to evaporate at room temperature for at last 48 hours.
  • Table 2 summarizes insulin-containing formulations.
  • Table 2 Insulin-containing ILFPM formulation
  • HPC 630 mg was first dissolved in ethanol (7 g) using a magnetic stirrer (500rpm) at 40°C-60°C.
  • CHL CHL-containing formulations
  • the CHL was added (34.3 mg) to the solution at the same temperature.
  • PC 270 mg or 235.7 mg for the formulations without and with CHL respectively
  • PE-fluorescein (1 mg) was separately dissolved in ethanol (2 ml) by hand shaking, at room temperature and the solution was then kept at 4°C in a vial covered with aluminum foil.
  • the confocal microscopy observations were performed using Confocal Laser Scanning Microscope, Zeiss 410.
  • the observations were performed on both dry and wet samples, where distilled water (3-5 drops) was used for wetting of the samples 5 minutes prior to the observation.
  • Example 5 Trapped volume determination:
  • the trapped volume of the spontaneously formed vesicles was determined by preparing ILFPM containing 6-caboxyfluorescein (6-FAM).
  • CHL (25.4 mg) was first dissolved in ethyl alcohol (9 g) at 40°C and then HPC (467 MG) was added to the solution. After complete dissolution of HPC, PC (Epikuron 200, 174.6 mg) was added and completely dissolved in the solution.
  • a solution of 6-FAM (1.3 ml, 31 ppm) in Tris buffer (pH 7.5) was added. In all cases the addition and dissolution of materials was carried out while stirring at room temperature. The solution was then cast into a polyethylene weighing plate and ethanol was allowed to undergo evaporation at room temperature for at least 48 hours.
  • the hydration of the 6-FAM containing films was performed using 1 ml of Tris buffer (25 ⁇ M). The hydrated films were then placed at 37°C for overnight (18 hours). The separation of spontaneously formed liposomes from the aqueous medium (supernatant) was carried out by centrifugation at 18000 rpm for 1.5 h at 20°C using a Sorvall Super T 21 centrifuge. The residues of the supernatant solution were carefully removed with a swab. The absorbance intensity of the trapped solution was measured after addition (1 ml) of Triton X-100 (10%).
  • the concentrations of both supernatant 6-FAM solution as well as trapped solution in precipitate were determined using a calibration curve prepared in the range of 0.0620-10.3300 ppm.
  • the absorbance measurements were performed spectrophotometrically at 480nm using HP 8452A Diode-Array.
  • the volume of the total internal aqueous compartment (Vi) of the vesicle was calculated from the amount of trapped solute, the concentration of the trapped solute in the supernatant (C1), and the molar concentration of phospholipid (CMpc) using the following correlation (Roseman, A. M., Lentz, B. R., Sears, B., Gibbes, D.,
  • Vi [C2*V2/(C1-C2)]/CMpc, where C2 is the concentration of trapped solute measured after addition of Triton, and V2 is the volume of Triton added to the precipitated liposomes.
  • the percent entrapment and entrapment efficiency were examined for several active materials representing each of the groups of very water soluble, intermediate, and very low soluble active materials.
  • the percent entrapment (A ⁇ _/A ⁇ * 100%) is defined as the total amount of drug/agent associated with the liposomes (AL), divided by the total amount of drug/agent used during the preparation of ILFPM (AT).
  • the entrapment efficiency is defined as the ratio between the concentration of encapsulated drug/agent and the concentration of lipid used in the ILFPM formulation.
  • the active material normally was added into the solution of ILFPM formulation and the solution was cast into a polyethylene weighing plate to result in a dry film which finally included the active material.
  • the concentration of active materials in both supernatant as well as the precipitate was determined using a HP 8452A Diode-Array Spectrophotometer at 260 nm, 328 nm, 248 nm, 280 nm, and 296 nm for sodium diclofenac, sulindac, flurbiprofen, DHE and sodium salicylate respectively.
  • the calibration curves obtained from the standard solutions, in intestinal fluid TS in the concentration range of 0-50 ppm, 2-60 ppm, 1-20 ppm, 0-30 ppm, and 2-20 ppm were respectively used for determination of sodium diclofenac, sulindac, flurbiprofen, DHE, and sodium salicylate concentrations.
  • the washing medium was buffer citric acid-NaOH-HCI at pH2, which was degassed by helium prior to use.
  • the separation was performed at room temperature. Fractions (20 fractions) with a volume of 1.45 ml were collected in each separation process.
  • Example 8 Gel permeation chromatography:
  • GPC Gel permeation chromatography
  • the GPC system consisted of a Waters 510 HPLC pump, a Waters 410 Differential Refractometer (at 40°C), a Waters 717 , Autosampler, and a Waters column heater (35°C).
  • a PL gel 5 ⁇ , 10 A column was used for GPC analysis.
  • LiChrosolv THF was used as mobile phase which was carefully degassed (by helium gas and sonication for 2 minutes) prior to use and filtered on-line through a Rheodyne inlet filter before the column.
  • the average diameter and size distribution of the ILFPM-based vesicles were measured using a sub-micron particle analyzer, Coulter model N4MD, with a size distribution processor analysis and multiple scattering angle detection. Approximately, but accurately, 1.5 mg of ILFPM sample was first suspended in 0.5 ml distilled water which was allowed to form a homogeneous suspension after completely dissolving HPC by either gently hand shaking or short Vortex shaking for varying period of times at room temperature. A volume of 10-50 ⁇ l, depending on the counts/sec of the instrument, was taken from the suspension and diluted by 3 ml of distilled water. The analysis was carried out at 25°C and dust (background) of 0% was obtained before the analysis. A viscosity of 0.849 CP and refractive index of 1.33 were considered throughout the analysis.
  • MTLFM modified thin lipid film
  • the principle of modified thin lipid film method is based on formation of drug/lipid film, by drying down of a phospholipid solution, and hydration of resulted thin lipid film by hand shaking.
  • the starting point was lipid solution preparation, which took place by the dissolving of phospholipid (100 mg of Epikuron 200) and the active material (20 mg) in ethanol (40 ml) in a 250 ml round-sided glass vessel.
  • glass beads (3.5 mm, 2 g) were added to the lipid/drug solution.
  • ILFPM formulations with and without CHL, 349-72/2, 349-72/1 respectively
  • Na-diclofenac as active material were used for this purpose.
  • the Na-diclofenac concentration was spectrophotometrically determined as mentioned for the entrapments assessment. Duplicate films were used for each period of time. The concentration of released active material in the supernatant was determined after centrifugation of the suspensions as described for drug entrapment assessment.
  • Example 13 Characterization of spontaneously formed liposomes: 13.1 TEM results:
  • FIG. 1 The typical electronmicrographs of negatively stained spontaneously formed liposomes from the wetting of ILFPM (formulations 349-47/9,10) are presented in figure 2.
  • Figure 2 indicates that the liposomes meshed spontaneously from ILFPM are normally oligo- or multilamellar. Multilamellar staining pattern is characteristic of phospholipids in the bilayer phase, suggesting that the membranes forming the walls consist of several phospholipid bilayers. It can be observed also that the walls of the vesicles usually appeared as broad poorly-defined bands, ranging in thickness from 160 to 450A. This multilamellar structure can also be formed for the vesicles prepared using the conventional "thin lipid film" method, as it can be seen in Figure 3.
  • MLVs are the main product obtained spontaneously upon the hydration of ILFPM, can be naturally predictable since MLVs have slightly higher free energies than hydrated precipitate (phospholipid aggregate) and significantly lower than both LUVs as well as SUVs. Therefore, MLVs are formed normally first upon the exposure of uncharged phospholipid to water or any aqueous media and in order to achieve LUVs and SUVs more energy (swirling, shaking, vortexing, sonicating etc.) must be dissipated into the system. This fact has been described in more detail elsewhere (Lasic, D. D., Biochem., J., 256, 1-11, 1988).
  • the aggregates of liposomes observed in Figure 2 can be the results of the spreading of monolayer liposomes embedded in negative stain across the grid. This is in fact the main problem of the negative staining electron microscopy method where the heavy metal stains lead to aggregation and possible re-organization of liposomes ("Liposomes, A Practical Approach", The Practical Approach, R. R. C).
  • the size and size distribution analysis of ILFPM-based liposomes were performed using a submicron particle analyzer.
  • the histograms illustrating the size distribution of the liposomes formed from HPC/PC (weight ratio of 7:3) and HPC/PC+cholesterol (weight ratio of 7:3) are presented in Figures 4 and 5 respectively.
  • the liposomes received from both formulations showed unimodal distribution with mean diameter of 1850 nm and 1300 nm for the former and the latter formulations respectively.
  • the SDP differential intensity results of both formulations showed, however, bimodal distribution. For instance the formulation which contained no cholesterol showed a large population of larger liposomes where most of the liposomes have diameter of 3550 nm and a smaller population of smaller liposomes having diameter of about 680 nm.
  • the confocal microscopy analysis was used to assess the mechanism of spontaneous vesicle formation from the ILFPM. It can be seen that upon the hydration of the system, first the dissolution of HPC takes place ( Figures 6-10) followed by destruction of the film and finally vesiculation of liposomes via transformation of phospholipid to tubular fibril ( Figures 11-23). Generally the first stage of the mechanism of vesicle formation is hydration of the phospholipid film. In the case of the conventional methods such as "thin lipid film” method by adding water to the dry phospholipid film the outer monolayer hydrates more than the inner ones.
  • HPC water soluble component
  • a water soluble component such as HPC enhances the process of water penetration into the system by reducing both the interfacial tension between the aqueous medium and the lipid component, as well as the energy of the system and causes the system to increase its specific surface area (Saupe, A., J. Colloid Interface ScL, 58, 549-558, 1975) ( Figures 6-10).
  • HPC is a surface-active polymer which can be compatible with surface active agents because of its hydroxypropyl substitution which imparts to the polymer some lipophilic nature. Water solutions of HPC display greatly reduced surface and interfacial tension.
  • the trapped volume (internal or capture volume) is expressed as the volume of the total internal aqueous compartment of the vesicle per unit quantity of lipid (I/mole lipid).
  • this trapped volume is determined by entrapping a water soluble-marker such as 6-carboxyfluorescein (6-FAM) and measurement of trapped 6-FAM amount as described in the materials and methods section.
  • 6-FAM for this purpose was based on the fact that it can interact neither with lipids components nor the polymeric matrix (HPC).
  • solution of 6-FAM with a predetermined concentration was added to ILFPM containing no fluorescein marker. The concentration of the supernatant obtained after centrifugation of the suspension was found to be identical to that of the initial used marker solution.
  • Example 16 The effect of active material content:
  • ILFPMs containing the same weight ratio of polymer to lipids but different active material contents were prepared and the entrapment and entrapment efficiency of Na-diclofenac were studied.
  • the hydration of the films was carried out using 5 ml of intestinal fluid TS and the films were allowed to undergo dissolution by hand shaking for 5 minutes at room temperature.
  • the results of % entrapment as well as entrapment efficiency are listed in table 4 and are illustrated in Figure 26. It can be seen that with increasing the active material content in the formulation, % entrapment decreases and the entrapment efficiency increases. It is also interesting to see the comparison between the results of the entrapment from formulations possessing the same weight ratio of active material/lipid but different lipid/HPC (tables 3 and 4).
  • Example 17 The effect of cholesterol content:
  • the spontaneous formation of liposomes can be initiated by exposing the ILFPM to an aqueous-based solution (hydrating medium).
  • aqueous-based solution hydrating medium
  • the liposome formation occurs simultaneously with the dissolution of HPC.
  • the content of the hydration medium is determined by the oral cavity's unique environment. This aspect should be considered where the oral cavity is used for a drug delivery and drug absorption site.
  • Various amounts of the buffer solution were added to the ILFPM and after complete dissolution of the film by hand shaking at room temperature, the entrapment as well as the entrapment efficiency of Na- diclofenac were determined. The results are listed in table 6. ILFPMs consisting of weight ratio of 66:24.7:3.6:5.7 of HPC:PC:CHL:AM or 66:28.3:5.7 of HPC:PC:AM were used in all cases. The results are shown in Figure 28.
  • the higher entrapment and entrapment efficiency resulting from using lower volume of hydrating medium can be ascribed to a lower leakage of Na-diclofenac from the inner liposome compartment upon dilution with the lower volume of the buffer. Likewise it can be the result of an efficient fusion of small vesicles during hydration with the lower volume of the buffer.
  • the minimal volume of hydrating medium can reduce osmotic gradients and thus less osmotic rupture of the vesicles during the hydration process (Bahrenholz, Y., Crommelin, D. J., "Encyclopedia of Pharmaceutical Technology", Swazbzick, J., Boylan, J.
  • the minimal volume of hydrating medium can also result in a slower rate of dissolution process of the polymer which can result in more effective vesiculation of the liposomes as well as concentrating the solute near the phospholipid membranes during hydration.
  • Example 19 The use of negatively-charged phospholipid and its effect on drug loading:
  • the principle of use of negatively-charged phospholipid is based on the fact that the internal trap of neutral phospholipid MLVs can be increased by incorporating charged lipids into the membrane. This takes place by increasing the electrostatic repulsion between bilayers thus inducing swelling (Rand, R. P., Annu. Rev. Biophys. Bioeng., 10, 277-314, 1981 , Gulik-Krzywicki, T., Rivas, E., Luzzati, V., J. MoI. Biol., 27, 303-322, 1967).
  • the procedures of the hydration as well as the measurement of the entrapment were the same as described for the solubility effect of active material.
  • the weight ratio of PC+PS/HPC is 27+3/70 (see table 1)
  • Example 20 The effect of temperature on entrapment:
  • the effect of temperature on entrapment is dependent on several variables such as the rate of the polymer dissolution, the rate of active material dissolution, partition coefficient of active material, the interaction between drug and phospholipid, the motion of fatty acid residues in the bilayers structure, the diffusion of drug from liposome (leakage) or into liposome, and the gel to liquid-crystalline phase transition (t m ) of phospholipid.
  • the phase change temperature of the various phospholipids is dependent on the chain length and the degree of saturation of the fatty acid components.
  • PC for ILFPM was based on the desire that the formation of the vesicles should be carried out spontaneously at physiological temperature and the fact that vesicles formation can be carried out only at a temperature which is above the gel to liquid crystal phase transition temperature of the phospholipid.
  • Both egg PC as well as soybean PC are in a liquid crystal state at room temperature owing to their content of unsaturated fatty acids.
  • the entrapment of HPC in the spontaneously formed liposomes was assessed using gel permeation chromatography method.
  • the HPC entrapment was determined by determining the amount of HPC in the precipitate obtained after centrifugation of the suspension obtained from the hydration of ILFPM, as it was mentioned in the section of "materials and methods".
  • the results of the entrapment of HPC from various formulations used for ILFPM preparation are listed in table 10.
  • Table 10 The entrapment of HPC in spontaneously formed liposomes from ILFPM
  • Emulgin LM-23 and then Insulin were dissolved in saline phosphate buffer pH 7.4. For improving dissolution, water purified was added.
  • Sodium laury sulphate (a) or sodium salicylate (b) or EDTA tetrasodium salt (c) were dissolved in saline phosphate buffer pH 7.4 and then Insulin was added.
  • Insulin, sodium laury sulphate, and then beta-cyclodextrin. were added into saline phosphate buffer pH 7.4.

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Abstract

L'invention concerne une composition solide de distribution intra-buccale d'insuline, qui contient: de l'insuline; une matrice polymère hydrophile; et un phospholipide qui permet une biodisponibilité de l'insuline d'au moins 5 %.
PCT/IL2006/000381 2005-03-31 2006-03-27 Composition solide de distribution intra-buccale d'insuline WO2006103657A2 (fr)

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EP1980240A1 (fr) * 2007-04-11 2008-10-15 Cephalon France Composition pharmaceutique lyophilisée et leurs procédés de fabrication et d'utilisation
EP2514406A1 (fr) * 2007-06-01 2012-10-24 Novo Nordisk A/S Préconcentrés spontanément dispersibles comprenant un médicament peptidique dans un support solide ou semi-solide
EP2526971A1 (fr) 2011-05-25 2012-11-28 ArisGen SA Administration de médicaments par les muqueuses
AU2009244797B2 (en) * 2008-05-07 2015-01-22 Merrion Research Iii Limited Compositions of peptides and processes of preparation thereof
WO2015188946A1 (fr) 2014-06-13 2015-12-17 Fricker, Gert Liposomes stabilisés par matrice
US9481721B2 (en) 2012-04-11 2016-11-01 Novo Nordisk A/S Insulin formulations
US9688737B2 (en) 2008-03-18 2017-06-27 Novo Nordisk A/S Protease stabilized acylated insulin analogues
US10010503B2 (en) 2008-08-18 2018-07-03 Entera Bio Ltd. Methods and compositions for oral administration
RU2665367C2 (ru) * 2014-11-12 2018-08-29 Общество с ограниченной ответственностью "Изварино Фарма" Пероральная система доставки вещества белковой природы (варианты), защитная оболочка системы доставки (варианты)
US10265385B2 (en) 2016-12-16 2019-04-23 Novo Nordisk A/S Insulin containing pharmaceutical compositions
US10265384B2 (en) 2015-01-29 2019-04-23 Novo Nordisk A/S Tablets comprising GLP-1 agonist and enteric coating
CN110464835A (zh) * 2018-05-11 2019-11-19 中国医学科学院药物研究所 一种胰岛素柔性微粒及其制剂
WO2020171727A3 (fr) * 2019-02-19 2020-11-12 Bluepharma - Industria Farmacêutica, S.A. Compositions mucoadhésives et leurs utilisations
WO2021029467A1 (fr) * 2019-08-14 2021-02-18 Sam Chun Dang Pharm. Co., Ltd. Forme posologique solide pour administration orale

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US9089484B2 (en) 2010-03-26 2015-07-28 Merrion Research Iii Limited Pharmaceutical compositions of selective factor Xa inhibitors for oral administration

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008127679A1 (fr) * 2007-04-11 2008-10-23 Cephalon, Inc. Compositions pharmaceutiques lyophilisées et procédés de fabrication et d'utilisation correspondant
EP1980240A1 (fr) * 2007-04-11 2008-10-15 Cephalon France Composition pharmaceutique lyophilisée et leurs procédés de fabrication et d'utilisation
EP2514406A1 (fr) * 2007-06-01 2012-10-24 Novo Nordisk A/S Préconcentrés spontanément dispersibles comprenant un médicament peptidique dans un support solide ou semi-solide
US9688737B2 (en) 2008-03-18 2017-06-27 Novo Nordisk A/S Protease stabilized acylated insulin analogues
US10259856B2 (en) 2008-03-18 2019-04-16 Novo Nordisk A/S Protease stabilized acylated insulin analogues
AU2009244797B2 (en) * 2008-05-07 2015-01-22 Merrion Research Iii Limited Compositions of peptides and processes of preparation thereof
US10010503B2 (en) 2008-08-18 2018-07-03 Entera Bio Ltd. Methods and compositions for oral administration
US10420721B2 (en) 2008-08-18 2019-09-24 Entera Bio Ltd. Methods and compositions for oral administration
US11246827B2 (en) 2008-08-18 2022-02-15 Entera Bio Ltd. Methods and compositions for oral administration
EP2526971A1 (fr) 2011-05-25 2012-11-28 ArisGen SA Administration de médicaments par les muqueuses
US9481721B2 (en) 2012-04-11 2016-11-01 Novo Nordisk A/S Insulin formulations
WO2015188946A1 (fr) 2014-06-13 2015-12-17 Fricker, Gert Liposomes stabilisés par matrice
RU2665367C2 (ru) * 2014-11-12 2018-08-29 Общество с ограниченной ответственностью "Изварино Фарма" Пероральная система доставки вещества белковой природы (варианты), защитная оболочка системы доставки (варианты)
US10265384B2 (en) 2015-01-29 2019-04-23 Novo Nordisk A/S Tablets comprising GLP-1 agonist and enteric coating
US10265385B2 (en) 2016-12-16 2019-04-23 Novo Nordisk A/S Insulin containing pharmaceutical compositions
US10596231B2 (en) 2016-12-16 2020-03-24 Novo Nordisk A/S Insulin containing pharmaceutical compositions
CN110464835A (zh) * 2018-05-11 2019-11-19 中国医学科学院药物研究所 一种胰岛素柔性微粒及其制剂
WO2020171727A3 (fr) * 2019-02-19 2020-11-12 Bluepharma - Industria Farmacêutica, S.A. Compositions mucoadhésives et leurs utilisations
WO2021029467A1 (fr) * 2019-08-14 2021-02-18 Sam Chun Dang Pharm. Co., Ltd. Forme posologique solide pour administration orale

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