WO2002064166A1 - Preparation permettant d'ameliorer la biodisponibilite des matieres bioactives et procede de preparation correspondant - Google Patents

Preparation permettant d'ameliorer la biodisponibilite des matieres bioactives et procede de preparation correspondant Download PDF

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Publication number
WO2002064166A1
WO2002064166A1 PCT/KR2002/000206 KR0200206W WO02064166A1 WO 2002064166 A1 WO2002064166 A1 WO 2002064166A1 KR 0200206 W KR0200206 W KR 0200206W WO 02064166 A1 WO02064166 A1 WO 02064166A1
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enhanced bioavailability
bioactive compounds
compounds according
group
peptides
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PCT/KR2002/000206
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English (en)
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Seo-Young Jeong
Ick-Chan Kwon
Hesson Chung
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Korea Institute Of Science And Technology
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Publication of WO2002064166A1 publication Critical patent/WO2002064166A1/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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a composition and a formulation to enhance bioavailability of bioactive materials and preparation method thereof. More particularly, the present invention relates to a composition comprising at least one monoglyceride, at least one emulsifier, organic solvents and aqueous solution and a liquid or powder formulation prepared by adding bioactive material with a low bioavailability to enhance bioavailability of bioactive materials and to acquire high encapsulation efficiency of the bioactive material and high storage stability for a long period of time and preparation method thereof.
  • Solubilization of materials can be applied to a variety of fields.
  • chemical processing where their catalysts, reactants, intermediates, etc. are water-insoluble materials
  • the solubilization of these materials will affect the yield and the direction of a given reaction.
  • Numerous Pharmaceutical compounds with good physiological activities are known to be insoluble in water and thus they have relatively low bioavailabilities. Because the solubilization of these Pharmaceutical compounds can simplify administration routes and increase pharmaceutical effects, the solubilization technology is essential in commercializing water-insoluble pharmaceuticals, and therefore extensive worldwide studies have been focused on developing the solubilization technology.
  • Cyclosporin and paclitaxel (Taxol ® ) are good Examples of water-insoluble Pharmaceutical compounds that cannot be administered alone due to their low solubilities.
  • Cyclosporin and paclitaxel are commercially available as pre-concentrates of Cremophor emulsion. These formulations can spontaneously form microemulsion upon dispersion in water (U.S. Pat. No. 5,438,072).
  • solubilizing formulations include emulsion or liposome, which uses lipid as a medium, and a polymeric nanoparticle or polymeric micelle, which uses a polymer as a medium (Langer, R. Nature, 392, 5-10, 1998).
  • lipid as a medium
  • the formulations using lipid as a medium are relatively advantageous in that their raw materials are biocompatible and thus they can be widely applied to medical fields including drug delivery systems.
  • the emulsions are heterogeneous mixture of oil and water by the use of emulsifiers.
  • the oil-in-water type emulsions composed of oil components dispersed in water, are widely used in solubilizing water-insoluble pharmaceutical compounds.
  • Liposome formulations consist of spherical lipid vesicles with lipid bilayers and water-insoluble Pharmaceutical compounds are enclosed within the lipid bilayer.
  • U.S. Pat. No. 5,531 ,925 discloses Cubosome®, another type of formulation using lipid as a solubilization medium, which was first developed by Swedish scientists in early 1990s. Cubosome® is prepared by dispersing the hydrated lipid cubic phase in water. The interior of Cubosome® comprises cubic phase wherein lipid and water components constitute continuous but separate three-dimensional channels, and there exists an interface between lipid headgroup and water.
  • Cubosome® could be advantageous over the conventional emulsion type or liposome type formulations, which only allow solubilization of hydrophobic and hydrophilic Pharmaceutical compounds, respectively, in that they can solubilize amphiphilic Pharmaceutical compounds as well as hydrophobic and hydrophilic Pharmaceutical compounds.
  • Cubosome® can be formed by first forming a very viscous liquid cubic phase by adding water and an emulsifier to monoglyceride, and then by dispersing the mixture in water.
  • Cubosome® has average particle size of as large as several micrometers in diameter with the aid of emulsifiers. Since it is preferential to have submicron-sized particles for the solubilization of Pharmaceutical compounds, it is also possible to obtain submicron-sized particles by applying mechanical forces such as microfluidization. Preparing submicron-sized Cubosome® particles by means of a mechanical force, however, may result in physicochemical instability of the enclosed materials or the constituting ingredients of the formulations due to high energy and high temperature accompanying the mechanical process.
  • the formulation process may also incur hydrolysis and oxidization of constituting ingredients because the enclosed materials or the constituting ingredients of the formulations may be vigorously mixed with air during the microfluidization process.
  • the dispersed Cubosome® prepared by the microfluidization process may experience the instability of the dispersion system after a prolonged storage and subsequently result in phase separation due to aggregation of particles.
  • Cubosome® type formulations have advantageous properties as described above over the conventional type of formulations, they also have disadvantages that they cannot encapsulate the thermally labile pharmaceutical compounds. Also, the physical and chemical stability of the formulation need to be improved greatly to provide a successful drug delivery system.
  • Peptide and proteins are physiologically active compounds and can be used as therapeutics with specific functions when compared to the molecules with smaller molecular weights. Proteins, however, cannot be orally administered since they are digested into amino acids by proteases inside the gastro-intestinal tract and lose the physiologically activity. The clearance rate of pharmaceutical proteins is also high in the blood stream when injected, causing great difficulties in administering the protein drugs.
  • Insulin is a drug that must be administered to the insulin dependent diabetes mellitus (IDDM) patients.
  • IDDM insulin dependent diabetes mellitus
  • IDDM insulin dependent diabetes mellitus
  • IDDM insulin dependent diabetes mellitus
  • IDDM insulin dependent diabetes mellitus
  • Successful oral insulin formulation will bring a revolutionary advancement in the treatment of IDDM.
  • many pharmaceutical companies and research groups have endeavored to make an oral insulin formulation with high bioavailability. Due to the limitations in the absorption of insulin in the gastrointestinal tract, however, it is only the beginning
  • peptide delivery systems have been developed. For instance, insulin was encapsulated inside liposomes or polymeric microspheres or administered together with protease inhibitors to prohibit the degradation of insulin.
  • the oral bioavailability could not be enhanced much, however, since the carriers such as liposomes have a relatively low encapsulation efficiency, and the insulin can also degrade during the encapsulation process.
  • Cyclosporin is the only peptide drug that can be administered orally. Cyclosporin is commercially available as pre- concentrates of Cremophor emulsion which can spontaneously form microemulsion upon dispersion in water (U.S. Pat. No. 5,438,072). There are no other oral peptide or protein formulations in the market, however, excepting the oral cyclosporin formulation. The main difficulty arises from the fact that peptide or protein is hard to be encapsulated inside a carrier, can be easily denatured and loses the pharmaceutical activity upon the storage even if it can be encapsulated in the carrier.
  • the present inventors have developed a solubilizing composition for insoluble drugs comprising a monoglyceride, an emulsifier and an organic solvent (Korea patent application 2000-12465) to overcome the problems of poor oral bioavailability.
  • the above solubilizing composition solubilizes various compounds, especially insoluble and amphiphilic substances effectively.
  • This liquid formulation can be easily dispersed in water, by shaking or vortexing, to form a dispersion of particles of less than 500 nm.
  • the above solubilizing composition can encapsulate most of the drugs efficiently even though the encapsulating efficiency depends on many factors including the molecular weight or hydrophobicity of the drugs. Peptides or proteins, however, cannot be solubilized in the above solubilizing composition since they do not mix with any of the components and forms precipitations.
  • the inventors of the present invention finally succeeded in preparing a homogeneous liquid composition comprising monoglycerides, emulsifiers, organic solvents, and water for enhanced bioavailability of bioactive compounds.
  • the present inventors also prepared a composition for enhanced bioavailability of bioactive compounds by adding and aqueous solution of peptide, protein or water-soluble polymers in the mixture of monoglycerides, emulsifier and organic solvent.
  • bioactive compounds including peptides, proteins and drugs for injection or external application by solubilizing and delivering the bioactive compounds efficiently inside the body and the preparation method thereof.
  • Another object of the present invention is to provide a powder composition for enhanced bioavailability of bioactive compounds prepared from the above liquid composition for enhanced bioavailability of bioactive compounds.
  • Yet another object of the present invention is to provide a powder formulation for enhanced bioavailability of bioactive compounds prepared by adding at least one bioactive compound with a low bioavailability into the above composition for enhanced bioavailability of bioactive compounds.
  • the present invention relates to a liquid composition for enhanced bioavailability of bioactive compounds comprising 9-90% by weight of at least one monoglyceride to increase bioavailability, 0.01-80 % by weight of at least one emulsifier, 0.01- 10 % by weight of aqueous solution to solubilize the bioactive compounds with a low bioavailability and 0.001-90.9 % by weight of at least one organic solvent.
  • the above monoglycerides are preferably selected from the group consisting of one or more saturated or an unsaturated monoglycerides having 10 - 22 carbon atoms in the hydrocarbon chain.
  • the content of the monoglycerides in the total amount of the liquid formulation is preferably 9 - 90 % by weight.
  • Monoglycerides is selected preferably from a group of consisting of monoolein, monopalmitolein, monomyristolein, monoelaidin, and monoerucin, and more preferably monoolein.
  • the emulsifier is preferably selected from the group consisting of a phospholipid, a sphingolipid, a non-ionic surfactant, an anionic surfactant, a cationic surfactant and bile acid.
  • the content of the emulsifier in the total amount of the liquid formulation is preferably 0.01 - 80 % by weight.
  • the phospholipid used as the above emulsifier is preferably selected from the group consisting of a phosphatidylcholine (PC) and its derivative, a phosphatidylethanolamine (PE) and its derivative, a phosphatidylsehne (PS) and its derivative and a polymeric lipid wherein a hydrophilic polymer is conjugated to the lipid headgroup.
  • PC phosphatidylcholine
  • PE phosphatidylethanolamine
  • PS phosphatidylsehne
  • the sphingolipid used as the above emulsifier is preferably selected from the group consisting of a ceramide, a cerebroside and a sphingomyelin.
  • the non-ionic surfactant used as the above emulsifier is preferably selected from the group consisting of a poloxamer (Pluronic: polyoxyethylene- polyoxypropylene copolymer), a sorbitan ester (Span), a polyoxyethylene sorbitan (Tween) and a polyoxyethylene ether (Brij).
  • the anionic surfactant used as the above emulsifier is preferably selected from the group consisting of a phosphatidylsehne (PS) and its derivative, a phosphatidic acid (PA) and its derivative and sodium dodecyl sulfate (SDS).
  • PS phosphatidylsehne
  • PA phosphatidic acid
  • SDS sodium dodecyl sulfate
  • the cationic surfactant used as the above emulsifier is preferably selected from the group consisting of 1 ,2- dioleyl-3-trimethylammonium propane (DOTAP), dimethyldioctadecylammonium bromide (DDAB), N-[1- (1 ,2-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1 ,2-
  • DOTAP dioleyl-3-trimethylammonium propane
  • DDAB dimethyldioctadecylammonium bromide
  • DOTMA N-[1- (1 ,2-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride
  • DOEPC dioleyl-3-ethylphosphocholine
  • the bile acid used as the above emulsifier is preferably selected from the group consisting of cholic acid, its salt and derivatives; deoxycholic acid, its salt and derivatives; ursodeoxycholic acid, its salt and derivatives; chenocholic acid, its salt and derivatives; and lithocholic acid, its salt and derivatives.
  • the aqueous solution to solubilize the bioactive compounds with a low bioavailability is preferably selected from the group consisting of water, an acidic solution including hydrochloric acid solution, phosphoric acid and acetic acid solution, a basic solution including sodium bicarbonate solution, and a biochemical buffer solution including phosphate buffered saline (PBS).
  • the content of the aqueous solution in the total amount of the liquid formulation is preferably 0.01 - 10 % by weight.
  • the organic solvent is selected from the group consisting of alcohol, ethyleneglycol, propylene glycol, polyethyleneglycol, dimethylsulfoxide, and the mixture of these solvents.
  • the organic solvent can be preferably selected from the group consisting of acetone, chloroform, benzene, toluene, acetonitrile, alcohols including octanol and the mixture of these solvents, when the said liquid composition is not used for in vivo drug delivery systems.
  • liquid formulation is preferably 1 ⁇ 90 % by weight.
  • the method of preparing the composition according to the present invention for enhanced bioavailability of bioactive compounds comprises the steps of:
  • CO- lt is preferable that the organic solvent in the first step of the above preparation method is selected from the group consisting of alcohol, ethyleneglycol, propylene glycol, polyethyleneglycol, dimethylsulfoxide, [or] and the mixture of these solvents.
  • the organic solvent in the second step of the above preparation method is selected from the group consisting of alcohol, ethyleneglycol, propylene glycol, polyethyleneglycol, dimethylsulfoxide, and the mixture of these solvents.
  • the organic solvent can be preferably selected from the group consisting of acetone, chloroform, benzene, toluene, acetonitrule, alcohols including octanol and the mixture of these solvents, when the said liquid composition is not used for in vivo drug delivery systems.
  • the present invention relates to a powder composition for enhanced bioavailability of bioactive compounds manufactured by lyophilization of the dispersion of the above liquid formulation for enhanced bioavailability of bioactive compounds by adding 0-30% (w/v) of a cryoprotectant.
  • the method of preparing the powder composition according to the present invention for enhanced bioavailability of bioactive compounds comprises the steps of:
  • step (2) 2) lyophilizing the dispersion in step (1) in the presence of cryoprotectant to prepare the powder formulation.
  • a cryoprotectant may be used to prevent the morphological changes of the particles in the dispersion of the above formulation during lyophilization, and it is preferable to add it less than 30% (w/v) to the liquid formulation.
  • cryoprotectant examples include sugars such as mannitol or trehalose, amino acids such as arginine, and proteins such as albumin.
  • the liquid and powder composition of the present invention can be easily dispersed in water mediated by such a minimal mechanical aid as a simply shaking with hands.
  • the size of particles is approximately 200 nm in general and can become as large as 500 nm depending on the property of a given emulsifier.
  • the present invention also provides formulations for enhanced bioavailability of bioactive materials as a drug delivery system.
  • the present invention provides a liquid and a powder formulation for enhanced bioavailability of bioactive materials and the preparation method thereof.
  • a liquid formulation for enhanced bioavailability of bioactive compounds according to the present invention comprises 0.001 - 50 % by weight of at least one bioactive compound with a low bioavailability as an
  • active ingredient 9 — 90 % by weight of at least one monoglyceride compound, 0.01-80 % by weight of at least one emulsifier, 0.01 - 10 % by weight of aqueous solution to solubilize the bioactive compound with a low bioavailability and 0.001 - 90 % by weight of organic solvent.
  • the kinds of monoglyceride compound, emulsifier, aqueous solution and organic solvent are identical as mentioned above.
  • peptides that can be used in the present invention include adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptides, bioadhesive peptides, Bradykinins and their related peptides, calcitonins and their related peptides, cell surface receptor protein fragments, chemotactic peptides, cyclosporins, cytokines, Dynorphins and their related peptides,
  • ACTH adrenocorticotropic hormone
  • angiotensin and its related peptides antibodies and their fragments, antigens and their fragments
  • atrial natriuretic peptides bioadhesive peptides
  • Bradykinins and their related peptides calcitonins and their related peptides
  • cell surface receptor protein fragments chemotact
  • enzyme inhibitors enzyme inhibitors, fibronectin fragments and their related peptides, gastrointestinal peptides, growth hormone releasing peptides, immunostimulating peptides, insulins and insulin-like growth factors, interleukins, luthenizing hormone releasing hormones (LHRH) and their related peptides, melanocyte stimulating hormones and their related peptides, nuclear localization signal related peptides, neurotensins and their related peptides, neurotransmitter peptides, opioid peptides, oxytocins, vasopressins and their related peptides, parathyroid hormone and its fragments, protein kinases and their related peptides, somatostatins and their related peptides, substance P and its related peptides, transforming growth factors (TGF) and their related peptides, tumor necrosis factor fragments, toxins and toxoids.
  • TGF transforming growth factors
  • Insulin as a peptide is preferably selected from a group consisting of a bovine pancreatic insulin, a human insulin, a human recombinant insulin, a porcine pancreatic insulin, an arg-insulin, an insulin-biotin, an insulin-FITC, LysPro (Eli Lilly) and a polyethylene glycol-insulin, (PEG-insulin).
  • the content of insulin in the total amount of the liquid formulation is preferably 0.01 - 20 % by weight.
  • the formulation of the present invention can comprise functional peptides such as anticancer peptides including angiostatins, antihypertension peptides, anti-blood clotting peptides, and antimicrobial peptides.
  • anticancer peptides including angiostatins, antihypertension peptides, anti-blood clotting peptides, and antimicrobial peptides.
  • the formulation of the present invention can comprise proteins such as immunoglobulins, angiogenins, bone morphogenic proteins, chemokines, colony stimulating factors (CSF) and their related proteins, cytokines, growth factors, interferons, interleukins, leptins, leukemia inhibitory factors, stem cell factors, transforming growth factors and tumor necrosis factors.
  • proteins such as immunoglobulins, angiogenins, bone morphogenic proteins, chemokines, colony stimulating factors (CSF) and their related proteins, cytokines, growth factors, interferons, interleukins, leptins, leukemia inhibitory factors, stem cell factors, transforming growth factors and tumor necrosis factors.
  • the above formulations can enclose a hydrophilic, a hydrophobic and an amphiphilic compound, especially a compound with a high molecular weight as a Pharmaceutical compound.
  • these Pharmaceutical compounds that can be used in the present invention are antivirals, steroidal anti-inflammatory drugs (SAID), non-steroidal anti-inflammatory drugs (NSAID), antibiotics, antifungals, vitamins, hormones, retinoic acid, prostaglandins, prostacyclins, anticancer drugs, antimetabolitic drugs, miotics, cholinergics, adrenergic antagonists, anticonvulsants, antianxiety agents, major tranquilizers, antidepressants, anesthetics, analgesics, anabolic steroids, estrogens, progesterones, glycosaminoglycans, polynucleotides, immunosuppressants and immunostimulants.
  • SAID steroidal anti-inflammatory drugs
  • NSAID non-steroidal anti-inflammatory drugs
  • antibiotics antibiotics
  • the above formulations can solubilize a hydrophilic and an amphiphilic polymer.
  • these polymers that can be used in the present invention are chitosan, alginic acid, alginate, hyaluronic acid, hyaluronate, polyethylene glycol and other functional polymers.
  • the preparation method of the above liquid formulation for enhanced bioavailability of bioactive compounds comprises the steps of:
  • step (1) After the evaporation, a trace of more than 0.001 % of volatile organic solvent of the total formulation is still present in the liquid formulation since the evaporation process does not require high vacuum.
  • a solvent mixture is used instead of a single solvent, only the volatile solvent is evaporated leaving involatile solvent in the final formulation.
  • the organic solvent in the first step of the above preparation method is selected from the group consisting of alcohol, ethyleneglycol, propylene glycol, polyethyleneglycol, dimethylsulfoxide, and the mixture of these solvents.
  • the organic solvent in the second step of the above preparation method is selected from the group consisting of alcohol, ethyleneglycol, propylene glycol, polyethyleneglycol, dimethylsulfoxide, and the mixture of these solvents.
  • the organic solvent can also be selected from the group consisting of acetone, chloroform, benzene, toluene, acetonitrule, alcohols including octanol when the said liquid composition is not used for in vivo drug delivery systems.
  • amount of the liquid formulation is preferably 0.001 — 90 % by weight.
  • the present invention provides a powder formulation for enhanced bioavailability of bioactive compounds manufactured by lyophilization of the dispersion of the above liquid formulation by adding 0-30% (w/v) of a cryoprotectant.
  • the preparation method of the above powder formulation comprises the steps of:
  • step (2) 2) lyophilizing said dispersion in step (1) in the presence of cryoprotectant.
  • a cryoprotectant may be used to prevent the morphological changes in the dispersion of the above formulation during lyophilization, and it is preferred to add it less than 30% (w/v) to the liquid formulation.
  • Preferred examples of a cryoprotectant include sugars such as mannitol or trehalose, amino acids such as arginine, and proteins such as albumin.
  • the liquid and powder formulation of the present invention can be easily dispersed in water mediated by such a minimal mechanical aid as a simply shaking with hands.
  • the size of particles is approximately 200 nm in general and can become as large as 500 nm depending on the property of a given pharmaceutical compounds or an emulsifier.
  • the constituting ingredients of and pharmaceutical compound in the particles are not degraded since a strong mechanical force is not required in generating the particles.
  • the above powder formulation dispersed easily in water before the intake.
  • the powder formulation can be dispersed in water for injection.
  • the formulations according to the present invention can be stored at room temperature in a sealed state for a long period of time without undergoing phase separation or the change in properties of the formulations.
  • the powder formulation is desirable because it does not contact with an organic solvent or moisture.
  • formulations of the present invention can be used as an
  • BSA bovine serum albumin
  • the size the polydispersity of the emulsion particles were measured by Photon Correlation spectroscopy (QELS method) using Malvern Zetasizer (Malvern Instruments Limited, England), and the polydispersity is a variance of the particle size in a logarithmic scale of a log-normal distribution function of the particle size.
  • the average particle size and polydispersity were obtained by measuring a given formulation three times (Orr, Encyclopedia of emulsion technology, 1 , 369- 404, 1985). This method was used in measuring the particle size and the polydispersity throughout the following Examples.
  • the above liquid formulations were dispersed well in water, and the average particle size and polydispersity were about 296.2 nm and 0.164, respectively.
  • Example 2 Preparation of Powder Formulation Containing Bovine Serum Albumin
  • 0.1 ml of the liquid formulation Containing Bovine Serum Albumin obtained in Example 1 1 ml of 5 % trehalose aqueous solution was added and solubilized completely by shaking. The mixture was lyophilized to prepare a powder formulation. The average particle size and polydispersity of the dispersion of the powder formulation were determined after dispersing approximately 3 mg of the above powder formulation in 3 ml of water or 0.01 M sodium deoxycholate as described in Example 1-2.
  • the above powder formulation was dispersed well in water, and, as indicated in the following table 1 , the average particle size and polydispersity of the dispersion of the powder formulation were 483.6 nm and 0.461 , respectively, in water and 170.0 nm and 0.276, respectively, in 0.01 M sodium deoxycholate.
  • liquid formulation were determined after dispersing approximately 10 ⁇ l or 75
  • the above formulation was dispersed well in water, and the average particle size and polydispersity of the dispersion of the liquid formulation were 303.9 nm and 0.185, respectively, in water and 175.2 nm and 0.377, respectively, in 0.01 M sodium deoxycholate.
  • the encapsulation efficiency of tetanus toxoid was determined as described in Example 1-2 except that the
  • the pneumococcal surface adhesin A (hereafter referred to "PsaA") dissolved in water was concentrated by using Sep-Pak Cartridges (Waters) to 0.5 mg/ml in methanol. In 1 ml of methanol, 10 mg of monoolein and 2 mg Pluronic F-68 or Pluronic F-127 were dissolved. The mixture was heated to
  • liquid formulation were determined after dispersing approximately 10 ⁇ l of the
  • Example 3 above liquid formulation in 3 ml of water, respectively, as described in Example 1-2.
  • the above formulation was dispersed well in water, and the average particle size and polydispersity of the dispersion of the liquid formulation are summarized in Table 3.
  • the encapsulation efficiency of PsaA was determined as described in Example 1-2 and was ca. 50 %.
  • Example 2 In 0.1 ml of the liquid formulation Containing PsaA obtained in Example 1 , 1 ml of 5 % trehalose aqueous solution was added and solubilized completely by shaking. The mixture was lyophilized to prepare a powder formulation. The average particle size and polydispersity of the dispersion of the powder formulation were determined after dispersing approximately 3 mg of the above powder formulation in 3 ml of water or 0.01 M sodium deoxycholate as described in Example 1-2.
  • liquid formulation were determined after dispersing approximately 10 ⁇ l of the
  • the above formulation was dispersed well in water, and the average particle size and polydispersity of the dispersion of the liquid formulation were 209.2 nm and 0.279, respectively.
  • the encapsulation efficiency of calcitonin was determined as described in Example 1-2 and was ca. 50 %.
  • a liquid insulin formulation was obtained by using the same procedure as described in Example 6 except that 3.0 mg of a growth hormone (somatotropin, from human pituitaries, 2 I.U./mg, Sigma) was used instead of calcitonin.
  • a growth hormone somatotropin, from human pituitaries, 2 I.U./mg, Sigma
  • the average particle size and polydispersity of the dispersion of the liquid formulation were determined after dispersing approximately 10 ⁇ l of the
  • the above formulation was dispersed well in water, and the average particle size and polydispersity of the dispersion of the liquid formulation were 234.9 nm and 0.224, respectively.
  • the encapsulation efficiency of PsaA was determined as described in Example 1-2 and was ca. 70 %.
  • liquid formulation were determined after dispersing approximately 10 ⁇ l of the above liquid formulation in 3 ml of water, respectively, as described in Example 1-2.
  • the above formulation was dispersed well in water, and the average particle size and polydispersity of the dispersion of the liquid formulation were 333.2 nm and 0.316, respectively.
  • the encapsulation efficiency of blue dextran was determined as described in Example 1-2 and was ca. 90 %.
  • the dispersion of the liquid and powder formulation according to the present invention has a particle size of less than 500 nm, a high solubilizing power of drugs and a high encapsulation efficiency of drugs.
  • the formulations according to the present invention can solubilize and encapsulate bioactive compounds with a low bioavailability such as peptides or proteins stably and also generate homogeneous particles less than 500 nm when dispersed in water. Moreover, the formulations can be easily dispersed in water without any mechanical aid, and problems such as phase separation, hydrolysis and oxidation, during long-term storage, can be prevented thus being suitable for use in drug delivery system.

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Abstract

L'invention concerne des compositions et des préparations permettant d'améliorer la biodisponibilité de matières bioactives et un procédé de préparation correspondant. Plus précisément, cette invention se rapporte à une composition contenant au moins un monoglycéride, au moins un émulsifiant, des solvants organiques, une solution aqueuse, une préparation liquide et en poudre préparée par addition de matières bioactives présentant une faible biodisponibilité afin d'améliorer la biodisponibilité de matières bioactives et d'obtenir une grande capacité d'encapsulation des matières bioactives et une stabilité de stockage élevée sur une longue période. L'invention porte aussi sur un procédé de préparation correspondant.
PCT/KR2002/000206 2001-02-13 2002-02-08 Preparation permettant d'ameliorer la biodisponibilite des matieres bioactives et procede de preparation correspondant WO2002064166A1 (fr)

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KR1020010007125A KR20020066778A (ko) 2001-02-13 2001-02-13 체내 난흡수 물질의 흡수촉진용 조성물과 제형 및 그의제조방법
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Cited By (50)

* Cited by examiner, † Cited by third party
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WO2002066014A2 (fr) * 2001-02-20 2002-08-29 The Procter & Gamble Company Compositions de cristal liquide cubique et procédé d'élaboration
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