WO2002013782A1 - Peptide a administration per os - Google Patents

Peptide a administration per os Download PDF

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Publication number
WO2002013782A1
WO2002013782A1 PCT/KR2000/000892 KR0000892W WO0213782A1 WO 2002013782 A1 WO2002013782 A1 WO 2002013782A1 KR 0000892 W KR0000892 W KR 0000892W WO 0213782 A1 WO0213782 A1 WO 0213782A1
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WO
WIPO (PCT)
Prior art keywords
proliposome
water
drug
preparation
peptide
Prior art date
Application number
PCT/KR2000/000892
Other languages
English (en)
Inventor
Hack-Joo Kim
Heung-Man An
Min-Jong Cha
Original Assignee
Hyundai Pharmaceutical Ind. Co., 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
Application filed by Hyundai Pharmaceutical Ind. Co., Ltd filed Critical Hyundai Pharmaceutical Ind. Co., Ltd
Priority to EP00952034A priority Critical patent/EP1311239A4/fr
Priority to CNA008198144A priority patent/CN1479609A/zh
Priority to AU2000264796A priority patent/AU2000264796A1/en
Priority to JP2002518929A priority patent/JP2004506003A/ja
Priority to CA002420032A priority patent/CA2420032A1/fr
Priority to PCT/KR2000/000892 priority patent/WO2002013782A1/fr
Publication of WO2002013782A1 publication Critical patent/WO2002013782A1/fr

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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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K9/1277—Processes for preparing; Proliposomes

Definitions

  • the present invention relates to a preparation for oral administration of peptide and protein drugs (hereinafter, referred to as "the peptide drug”) and a method for producing the same.
  • the peptide drug can be formulated in the most suitable form for administration to the patient, 2) the stability of the preparation is increased so that the conditions of production, selling and consumption such as distribution, establishment of the effective period, etc. can be conveniently and advantageously varied as compared to the prior formulation, and 3) the market of the oral preparation preferred by the patient will rapidly substitute for the market of prior drug formulations. Therefore, the technical study to develop the oral preparation has been actively made.
  • the major problems to be solved include 1) a low absorption in intestinal tract, 2) a loss of efficacy by proteinase present in small intestine and 3) a difficulty in maintaining the efficacy due to a short half-life within a living body after absorption and thus, the study places the focus such problems.
  • a liposome has been utilized as one method for developing the oral preparation of such peptide drugs.
  • This method has some advantages that 1) the drugs can be relatively readily included in a nano- or microsphere particle and 2) a liposome can be easily absorbed in intestinal mucous membrane, and therefore, has been widely studied in recent years.
  • Prior arts relating to such method include a technique disclosed in a patent by Lipotec, S.A. (EP-0855179 A2).
  • the present invention provides a method for improving the problems involved in the prior art as mentioned above, in which 1) water-soluble chitosan is used to prepare proliposome as the precursor of liposome thereby increasing the absorption into intestinal mucous membrane, 2) an agent for controlling pH is used to increase a stability of peptide drugs in aqueous intestinal juice, 3) an additive such as absorption accelerator, etc. is added in order that peptide drugs can be smoothly absorbed into intestinal mucous membrane, and then 4) the product is formulated into a preparation suitable to oral administration and at the same time, 5) the preparation is covered with an enteric coating so that the drug can be readily migrated and absorbed into the intestine without destruction.
  • the present invention can prepare a proliposome, as the precursor of liposome, in a high yield within a short time without conducting the procedure for lyophilization or evaporation in order to prepare liposome in the form of a powder, which may cause the problems occurring in the prior method for preparing the oral preparation using liposome as disclosed in EP-0855179, and therefore, has some advantages that the procedure of the process is simple, a stability of peptide drugs to moisture and temperature, which constitutes the disadvantage of peptide drugs, is increased, and chitosan is used as a carrier for preparing proliposome to increase a bioavailabilty.
  • the organic solvent is used to prepare the peptide drug coated onto water-soluble chitosan in the form of a powder; 2) an enteric coating is applied to the drug in order to protect the peptide drug from gastric acid;
  • the powdery proliposome in the form of a powder forms a liposome within the intestine owing to the physical property of water- soluble chitosan to be dissolved in water, so that the drug can be smoothly absorbed into intestinal mucous membrane and at the same time, chitosan having a free cation provides a property of attaching to intestinal mucous membrane;
  • an agent for controlling pH level is added to increase a stability of the drug in the intestine by taking an advantage that the most of peptide drugs are stable at pH level of 3 to 4;
  • an additive such as absorption accelerator is combined so that the peptide drugs can be easily absorbed into intestinal mucous membrane.
  • Chitosan is a natural high molecular material and is a substance made from polysaccharide chitin which is widely distributed in shells of crustacean such as crab, shrimp, etc. and insect outer skins, mushrooms, cell walls of fungi and plays a role of supporting and preventing the living body containing them.
  • chitin is a high molecular material in a very long chain structure without side chains, which is similar to celluloses, wherein carbon atom at 2-position is substituted with acetylamino radical (-NHCOCH 3 ) in place of hydroxyl radical (-OH).
  • Chitosan is a material produced by deacetylation of acetyl radical attached to amino group present on carbon atom at 2-position in chitin and can have a lot of free cations so that it possesses various physiological activities. For this reason, chitosan in a high quality has been developed and widely used in various industrial field such as food, cosmetics, pharmaceuticals and absorbents, activating agent for plant cells, aggregating agent for waste water disposal, etc.
  • chitosan which has been widely used in various field in these days cannot be dissolved in water or an alcohol but can be dissolved only in an aqueous solution of an organic acid such as formic acid, lactic acid, acetic acid, etc., or an inorganic acid such as dilute hydrochloric acid, it has the limited applicability in the field of pharmaceutical preparations.
  • Water-soluble chitosan used in the present invention is characterized in that 1) the degree of deacetylation is 85%-99%, 2) the solubility in water is 99.99% or more, 3) the molecular weight is 100,000 to 500,000 to be possibly used as the excipient in pharmaceutical products, and 4) it meets the standard requirements for a food additive.
  • the major characteristic feature of chitosan used in the present invention is the water solubility of 99.99% or more.
  • the reasons why the water solubility of chitosan used in the present invention is higher than that of the prior chitosan are that 1) the method for preparing chitosan by treating chitin with an aqueous alkaline solution, and conducting deacetylation procedure by hydrolyzing acetylamino group to amino group followed by a multi-step separation membrane procedure allows an increase in the degree of acetylation to 85 - 99 % while maintaining the water-solubility of chitosan, 2) chitosan can be prepared in a purity of 90% or more through a multi-step separation membrane procedure, and 3) since amino group is activated during the deacetylation procedure for carbon atom at position 2 of chitosan, chitosan can be readily dissolved in water while maintaining the characteristic properties of chitosan when chitosan is contacted with water molecules.
  • the characteristic feature of the present invention is to prepare the oral preparation of peptide drugs by removing the problems of liposome which has been used in the field of pharmaceuticals and cosmetics and simultaneously taking advantages of water-soluble chitosan which can be dissolved in an aqueous solution while reserving the advantages of chitosan.
  • liposome since in 1965 liposome was reported as a mono-layer or multi-layer phospholipid double-membrane closing vesicle by Bamgham et al., (Diffusion of Univalent Ions across the Lamellae of Swollen Phospholipids, J. Mol. Biol., 13, 238-252, 1965), during the past scores of years liposome has been prepared according to numerous methods for preparation thereof by modifying 1) a surface charge, 2) a size and 3) a lipid content so as to meet with the use purpose and end use of liposome, and used in food, cosmetics and pharmaceutical products.
  • liposome has been used in the pharmaceutical field to develop various pharmaceutical formulation for the purpose of 1) the sustained activity and targeting of the drug, 2) the alleviation of acute toxicity and the alleviation or enhancement of immunoreaction, 3) the stabilization of the drug and 4) the change of dosage formulation.
  • liposomes which have been utilized for development of pharmaceutical formulations have disadvantages insufficient to be effectively used in the pharmaceutical products that their stability in the aqueous solution is low due to the properties of liposome itself including 1) aggregation, 2) sedimentation, 3) fusion, 4) oxidation and 5) phospholipid hydrolysis, and 6) the efficiency of sterilization and reproductibility during the process for mass production is low.
  • the purpose of the present invention is to provide a proliposome of the peptide drug prepared by using a water-soluble chitosan.
  • Another purpose of the present invention is to provide an oral preparation formulated from a proliposome of the peptide drug produced using a water-soluble chitosan according to a conventional pharmaceutical method.
  • Further purpose of the present invention is to provide a process for preparing an oral preparation formulated from a proliposome of the peptide drug produced using a water-soluble chitosan according to a conventional pharmaceutical method.
  • the carrier for preparing proliposome must have the following properties: 1) it must be water-soluble since it is dissolved in water to be converted into liposome from proliposome, and 2) its solubility in the organic solvent used in the course of the process must be low.
  • Water-soluble chitosan used in the present invention not only has the carrier properties of proliposome as mentioned above but also can increase the absorption of peptide drug in the living body in case of the oral administration of the drug due to an effect of increasing the adhesive property caused by an ability of free cations contained in chitosan itself to combine with lipid when it is dissolved by the action of water within the intestine.
  • other peptide and protein drugs can also be included within the scope of the present invention.
  • Phospholipids used in preparing the proliposome containing peptide drug according to the present invention include a pharmaceutically acceptable phospholipid conventionally used for preparation of liposome, for example, phosphatidyl-DL- glycerol-dimyristoyl, L- ⁇ egg phosphatidyl choline, soybean phosphatidyl choline (lecithin), dipalmitoyl phosphatidyl choline (DPPC), dimyristoyl phosphatidyl choline (DMPC), cholesterol, stearylamine, diacetylphosphate, phosphatidyl serine, methoxypolyethylene glycol distearoyl phosphatidyl-ethanolamine, etc.
  • a pharmaceutically acceptable phospholipid conventionally used for preparation of liposome for example, phosphatidyl-DL- glycerol-dimyristoyl, L- ⁇ egg phosphatidyl choline, soybean phosphatidyl choline
  • the peptide drugs composed of amino acids are generally contain asparagines or glutamine residue in their structure and these residues occur the reaction such as deamidation, beta-elimination, disulfide exchange, racemization, oxidation, etc., which may readily induce the structural degeneration to ultimately cause the lose of an activity as peptide drugs.
  • the present invention uses an agent for controlling pH level to pH 3-4 at which asparagines and glutamine residues do not occur chemical reaction when the oral preparation according to the present invention is readily dissolved in the intestine, to stably maintain the peptide drugs in the intestine.
  • any agent which can be generally used for oral administration in the pharmaceutical products can be used and the typical example thereof includes citric acid, sodium citrate, adipic acid, sodium monohydrogen phosphate, etc.
  • the agent for controlling pH level is preferably used in an amount of 1.0% to 50% on the basis of the total amount.
  • Another characteristic feature of the present invention is to stimulate the absorption of peptide drugs into the small intestine when the drug is administered via oral route, by using the absorption accelerator originated from natural products or food products which do not cause any damage to the epithelial cells of intestinal tract.
  • the absorption accelerators which can be used in the present invention include fatty acids or salts thereof such as capric acid, oleic acid, etc., cholate as the salt of bile acid, deoxycholic acid, salicylate-based absorption accelerator, or monoglyceride-based absorption accelerator.
  • the absorption accelerator generally used in Example part of the present invention is preferably deoxycholate as the cholic acid-based salt which is preferably used in an amount of 0.1% to 10%.
  • Figure 1 is a photograph showing a shape of the proliposome formed from salmon calcitonin and water-soluble chitosan and the inclusion of the drug;
  • Figure 2 is a photograph showing the process of dissolution in water as obtained from observation of the hydration process of the proliposome using water-soluble chitosan by mean of a microscope, wherein Figure 2a is a photograph showing proliposome powder and Figure 2b is a photograph showing the production of liposome from proliposome;
  • Figure 3 is a graph showing the particle size and distribution of liposome formed from hydration of the proliposome
  • Figure 4 is a graph showing a change in the content of salmon calcitonin in the proliposome of salmon calcitonin, as one embodiment according to the present invention, in course of time;
  • Figure 5 is a graph showing the drug permeability of various formulations containing the proliposome of salmon calcitonin, as one embodiment according to the present invention.
  • 3g of water-soluble chitosan powder (106 ⁇ m - 300 ⁇ m) passed through a sieve was introduced into a 100 ml round-bottomed flask, mounted on a rotary evaporator and then dried under reduced pressure for 30 minutes at room temperature.
  • 160 mg of phosphatidyl-DL-glycerol-dimyristoyl as phospholipid was dissolved in 24 ml of chloroform and then mixed with a solution of 20 mg of desmopressin, which was previously dissolved in 12 ml of ethanol.
  • the respective drug selected from the group consisting of aprotinin, buserelin, elcatonin, glucagon, gonadotropin, gonadorelin, goserelin, hirudin, leuprolein, lypressin, nafarelin, octreotide, oxytocin, protirelin, salcatonin, sermorelin, somatostatin, somatropin, terlipressin, tetracosacrin, thymopentin, triptorelin, vasopressin, albumin, insulin, interferon, immunoglobulin, GM-CSF, G-CSF and glycoprotein was used according to the similar method to Example 1 or 2 to prepare the corresponding proliposome containing respective peptide drug.
  • the proliposome not including the drug and the proliposome including the drug were comparatively observed by means of an ultra-low temperature electron microscope.
  • pretreatment of the sample first, one drop (about 3 ⁇ l) of the liquid sample (liposome hydrated from proliposome) was dropped on a discus sample table having a diameter of 1 cm, and liquid nitrogen was filled in a nitrogen slushing chamber of Cryo-transfer system (CT 1500 Cryotrans, Oxford Instrument Ltd., UK). Then, the sample was rapidly introduced in the chamber and fixed for one minute in vacuum.
  • the sample was transferred to a cryo-chamber controlled to -170°C and the vacuum state was confirmed. Then, the cooled sample was voluntarily broken and cleaved, and the resulting broken sample was transferred to a sample table of a scanning electron microscope (JSM-5410LV, JEOL LTD., Japan) connected to the cryo-transfer system and the temperature was controlled to -70°C at which the sample was maintained for 5 minutes to sublimate the moisture form the sample surface.
  • JSM-5410LV scanning electron microscope
  • proliposome granules were mounted on a slide of the microscope and the focus was adjusted. At 400X magnifications, one drop of water was dropped on the granule and after one minute the hydration process could be observed to confirm the dissolution process of the proliposome in water of which the photograph is shown in Figure 2.
  • the prepared proliposome corresponding to about 5 ⁇ g of salmon calcitonin was accurately weighed, dissolved in 300 ⁇ l of methanol and then completely dissolved with vortex. After filtration through a 0.45 ⁇ m filter, an aliquot of 40 ⁇ l was applied to HPLC to quantify the content of salmon calcitonin in the proliposome.
  • the result from determination of the stability at room temperature and under refrigerator is shown in Figure 4.
  • the conditions for HPLC utilized for analyzing the content of the drug are as follows:
  • HPLC conditions Column - C 18 (Sucelpo Inc.) Flow rate - 1 ml/min.
  • the tablet was prepared by a direct compression in the manner of dry process rather than wet process according to the general method for preparing a tablet as defined in the part of General Provisions For Preparation in the Korea Pharmacopoeia.
  • the compositions of respective samples prepared in order to examine the effect of the present invention are shown in the following Table 1 and the respective samples prepared by a direct compression were coated with Cellulose Acetate phthalate(CAP) to provide an enteric coating.
  • CAP Cellulose Acetate phthalate
  • the pH level was adjusted with 1 N hydrochloric acid to 7.4 by means of a pH- meter.
  • the solution was filtered through a filter (Corning Filter 430015) and then dispensed into 500 ml bottles 450 ml in each bottle by means of a 50 ml pipette.
  • the complete medium which was prepared and then preserved in a refrigerator, was warmed in a water bath at 37°C for about 20 minutes and then mixed for 4 to 5 times using a 5 ml pipette. 5 ml of the medium was then introduced into a 15 ml centrifuge tube.
  • Cell line (ATCC HTB-37, LOT 944495) was taken out of a nitro tank and thawed in a water bath at 37°C with slightly opening a cap of the bottle. After identifying that the cell line was completely thawed, the cap of the bottle reserving cell line was opened and mixed 5 to 6 times with a 5 ml pipette. The whole content of the bottle was introduced into the above 15 ml centrifuge tube.
  • the whole content of the solution contained in 15 ml conical tube was transferred to a 25 ml T-flask that was then preserved in an incubator.
  • a 25 ml T-flask which was preserved in the incubator was taken out of the incubator and the media on the bottom of the flask was removed and replaced by warming the compete medium, which was previously prepared and preserved in a refrigerator, in a water bath at 37°C for about 20 minutes and then introducing 5 ml aliquot of the medium into 25 ml T-flask with taking care of not touching the pipette with the bottom of the flask.
  • Trypsin EDTA was allowed to uniformly distribute and the flask was then preserved in a water bath at 37°C for 4 minutes. 10 ml of the complete medium was added to 25 ml T-flask and the flask was shaken to separate the cells. The separated solution was transferred to 15 ml conical tube by means of a pipette, centrifuged at 1000 rpm for 5 minutes to remove the supernatant. 2 ml of the complete medium was added to T-flask and the cells were allowed to be well loosen and then re-incubated in the incubator (In this experiment, the cells over 40 passages were used.).
  • 0.5 ml and 1.5 ml of the complete medium were introduced into the upper compartment and the lower compartment, respectively, of the coated transwell and incubated for 15 minutes in the incubator. Then, the medium was removed and 1.5 ml of the complete medium was re-introduced into the lower compartment of the re-coated transwell. Cells over 40 passages under subculture were diluted to the concentration of 2.5-3 x 10 5 cells/ml and then introduced into the upper compartment of the coated transwell in an amount of 1.5 ml and incubated for 2 to 3 weeks so as to be used in the experiment.
  • transepithelial electrical resistance was measured by means of a Millicell-ERS Resistance System to confirm the resistance of 250 ⁇ cm 2 or more which means that the monolayer of cells was well established.
  • TEE transepithelial electrical resistance
  • Drug concentration as used 2-10 ⁇ M of C 14 -mannitol having a specific activity of 50 mCi/mmol
  • the examined medium present in the upper compartment of the transwell was removed using a pipette.
  • the proliposome prepared in Example 1 above was dissolved in a transbuffer to the concentration of the drug (4.0 ⁇ g/ml) and then introduced into the upper compartment of the transwell, which was transferred to the new well containing a flashbuffer in intervals of 15 minutes after addition of the drug while slowly shaking at 85 rpm in a shaking water bath of 37°C.
  • the drug was sampled from the well in the donor part of transwell and then quantitatively analyzed with respect to salcatonin by means of ELISA and RIA kit (Pen. Lab.). The result is shown in Figure 5.
  • the collected blood was centrifuged in a centrifuge at 10,000 rpm for 10 minutes to separate the supernatant from which the content of the drug was quantified using ELISA and RIA Kit (Pen. Lab.).
  • the same amount of the drug as orally administered was injected to femoral vein and the blood was pre-treated according to the similar manner to the method for collecting blood in case of each formulation. Then, the drug was quantified to calculate the bioavailability, which is described in the following Table 3.
  • the present invention provides a method wherein 1) water-soluble chitosan is used to prepare proliposome as the precursor of liposome thereby increasing the absorption into intestinal mucous membrane, 2) an agent for controlling pH is used to increase a stability of peptide drugs in aqueous intestinal juice, 3) an additive such as absorption accelerator, etc. is added in order that peptide drugs can be smoothly absorbed into intestinal mucous membrane, and then 4) the product is formulated into a preparation suitable to oral administration and at the same time, 5) the preparation is covered with an enteric coating so that the drug can be readily migrated and absorbed into the intestine without destruction.
  • the present invention can prepare a proliposome, as the precursor of liposome, in a high yield within a short time without conducting the procedure for lyophilization or evaporation in order to prepare liposome in the form of a powder, which may cause the problems occurring in the prior method for preparing the oral preparation using liposome as disclosed in EP-0855179, and therefore, has some advantages that the procedure of the process is simple, a stability of peptide drugs to moisture and temperature, which constitutes the disadvantage of peptide drugs, is increased, and chitosan is used as a carrier for preparing proliposome to increase a bioavailabilty.

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Abstract

La présente invention concerne un proliposome de médicament à base de peptidyle et des préparations entériques contenant ledit proliposome. Pour obtenir ce proliposome, on dissout le médicament à base de peptidyle avec un phospholipide dans un solvant organique, puis on recouvre la solution ainsi obtenue de chitosane hydrosoluble. Ce système d'administration per os de peptide faisant intervenir le proliposome et les préparations entériques selon l'invention permet d'augmenter considérablement la stabilité et la biodisponibilité des médicaments à base de peptidyle.
PCT/KR2000/000892 2000-08-11 2000-08-11 Peptide a administration per os WO2002013782A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP00952034A EP1311239A4 (fr) 2000-08-11 2000-08-11 Administration orale de peptide
CNA008198144A CN1479609A (zh) 2000-08-11 2000-08-11 肽的经口递送
AU2000264796A AU2000264796A1 (en) 2000-08-11 2000-08-11 Oral delivery of peptide
JP2002518929A JP2004506003A (ja) 2000-08-11 2000-08-11 ペプチドの経口デリバリー
CA002420032A CA2420032A1 (fr) 2000-08-11 2000-08-11 Peptide a administration per os
PCT/KR2000/000892 WO2002013782A1 (fr) 2000-08-11 2000-08-11 Peptide a administration per os

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2000/000892 WO2002013782A1 (fr) 2000-08-11 2000-08-11 Peptide a administration per os

Publications (1)

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WO2002013782A1 true WO2002013782A1 (fr) 2002-02-21

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EP (1) EP1311239A4 (fr)
JP (1) JP2004506003A (fr)
CN (1) CN1479609A (fr)
AU (1) AU2000264796A1 (fr)
CA (1) CA2420032A1 (fr)
WO (1) WO2002013782A1 (fr)

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WO2001082897A2 (fr) * 2000-05-02 2001-11-08 Enzrel, Inc. Administration de medicaments a l'aide de liposomes
US6824790B2 (en) 2002-01-09 2004-11-30 Enzrel Inc. Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds
JP2005298407A (ja) * 2004-04-12 2005-10-27 Masahiko Abe ポリカチオン修飾リポソームおよびその製造法
WO2006062506A1 (fr) * 2004-12-03 2006-06-15 Enzrel, Inc. Administration de composes antioxydants ou anti-inflammatoires au moyen d'un medicament liposomal enrobe de chitosane
CN100371018C (zh) * 2003-06-12 2008-02-27 刘青松 降钙素组合物
WO2009149537A1 (fr) * 2008-06-12 2009-12-17 Christine Allen Mélange polymère-lipide injectable
US8658202B2 (en) 2001-04-25 2014-02-25 Western University Of Health Sciences Coated drug delivery formulations
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CN105902400A (zh) * 2016-06-17 2016-08-31 江山 一种包裹生物酶的微粒及其制备方法和应用
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CN103127003B (zh) * 2013-03-19 2014-05-07 广东彼迪药业有限公司 一种奥美拉唑肠溶微丸、胶囊及其制备方法
CN114010801B (zh) * 2021-11-16 2023-09-26 上海理工大学 一种l-抗坏血酸棕榈酸酯修饰的小分子肽脂质体及其制备与应用
CN114081963B (zh) * 2021-11-16 2023-09-26 上海理工大学 一种提高活性肽生物利用度的纳米载体及其制备与应用

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ES2130056B1 (es) * 1997-01-16 2000-02-01 Lipotec Sa Un nuevo preparado farmaceutico para mejorar la biodisponibilidad oral de drogas de dificil absorcion.

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Title
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TAKEUCHI ET AL.: "Enteral absorption of insulin in rats from mucoadhesive chitosan-coated liposomes", PHARM. RES., vol. 13, no. 6, 1996, pages 896 - 901, XP002055070 *
TAKEUCHI ET AL.: "Mucoadhesive liposomes coated with chitosan or carbopol for oral administration of peptide drugs", PROC. INT. SYMP. CONTROLLED RELEASE BIOACT. MATER. 26TH, 1999, pages 988 - 989, XP002964493 *

Cited By (18)

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JP2004506003A (ja) 2004-02-26
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EP1311239A1 (fr) 2003-05-21
EP1311239A4 (fr) 2005-06-22
CN1479609A (zh) 2004-03-03

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