CA2195881C - Stabilization of colloidal systems through the formation of lipid-polysaccharide complexes - Google Patents
Stabilization of colloidal systems through the formation of lipid-polysaccharide complexes Download PDFInfo
- Publication number
- CA2195881C CA2195881C CA002195881A CA2195881A CA2195881C CA 2195881 C CA2195881 C CA 2195881C CA 002195881 A CA002195881 A CA 002195881A CA 2195881 A CA2195881 A CA 2195881A CA 2195881 C CA2195881 C CA 2195881C
- Authority
- CA
- Canada
- Prior art keywords
- weight
- process according
- phospholipid
- systems
- oil
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
-
- 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
-
- 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
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
- Y10S977/797—Lipid particle
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
- Y10S977/797—Lipid particle
- Y10S977/798—Lipid particle having internalized material
- Y10S977/799—Containing biological material
- Y10S977/801—Drug
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
- Y10S977/907—Liposome
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/915—Therapeutic or pharmaceutical composition
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/926—Topical chemical, e.g. cosmetic or sunscreen
Abstract
Stabilization of colloidals systems through the formation of ionic lipid- polisaccharide complexes. There is disclosed a process for the preparation of colloidal systems which includes the incorporation of a water soluble and positively charged amino polysaccharide and a negatively charged phospholipid. The colloidal systems (which comprise polymer nanoparticles, nanocapsules and nano-emulsions) are stabilized through the formation of a ionic complex, at the interface, comprised of the aminopolysaccharide and the phospholipid. The colloidal systems are characterized in that they have a particle size lower than 1 .mu.m, an electric positive charge and an exeptional stability during storage. They are lyophilizable so that they can be dry stored and redispersed subsequently while maintaining the original characteristics of the system. They are useful as pharmaceutical forms for the oral, transdermic, topical, ocular, nasal and vaginal administration of medicaments. They are also useful as forms for cosmetic us e.
Description
21~~J~1 STABILI7AT10N OF COLLOIDAL SYSTEMS TIIROUGIi TIIE FORMATION OF
LIPID-POLYSSACI-iARIDE COMPLEXES
Stabilization of colloidal systems through the formation of lipid-polyssacharide complexes. Development of a procedure for the preparation of colloidal systems involving a combination of two ingredients: a water soluble and positively charged polyssacharide and a negatively charged phospholipid. The procedure can be applied to the stabilization of colloidal systems of pharmaceutical and cosmetic use. These systems include oil-in-water submicron emulsions, nanocapsules consisting of an oily core surrounded by a polymer coating and polymeric solid nanoparticles. The common feature to all these colloidal systems is that they consist of a dispersed phase -oily nanodroplets, nanocapsules or nanoparticles-and a contW uous aqueous phase. The originality of the procedure relies on the incorporation of lecithin (anionic ingredient), as a lipophilic surfactant, in the dispersed phase and of the chitosan, as a hydrophilic suspending agent, in the continuous aqueous phase.
Lecithin is a natural surfactant composed of a mixture of various phospholipids. The mayor compound is phosphatidylcholine (phospholipid of a neutral character) and the secondary compounds are phosphatidylethanolamine, phosphatidylserine and phosphatidic acid (phospholipids with a negative charge). Presently, there are several types of lecithin available in the market. They differ in their origin and in their phosphatidylcholine content.
Chitosan is a natural polymer obtained by a deacetatilation process of the chitin (compound extracted from the crustacean shells). Chitosan is an aminopolysaccharide and has a positive charge. Presently, there are several types of chitosan available in the market. They differ in their molecular weight, deacetilation degree and the type of salt or acid form.
The colloidal systems covered in this patent are characterized because they contain lecithin and chitosan in their composition and they have a positive charge and an improved stability. Other ingredients will be specific of the type of system i.e. an oil, in the case of the submicron emulsions; an oil and a hydrophobic polymer, in the case of the nanocapsules, and a hydrophobic polymer in the case of the nanoparticles. Drugs, proteins and other bioactive compounds of interest in medicine and cosmetics can be incorporated in these systems.
LIPID-POLYSSACI-iARIDE COMPLEXES
Stabilization of colloidal systems through the formation of lipid-polyssacharide complexes. Development of a procedure for the preparation of colloidal systems involving a combination of two ingredients: a water soluble and positively charged polyssacharide and a negatively charged phospholipid. The procedure can be applied to the stabilization of colloidal systems of pharmaceutical and cosmetic use. These systems include oil-in-water submicron emulsions, nanocapsules consisting of an oily core surrounded by a polymer coating and polymeric solid nanoparticles. The common feature to all these colloidal systems is that they consist of a dispersed phase -oily nanodroplets, nanocapsules or nanoparticles-and a contW uous aqueous phase. The originality of the procedure relies on the incorporation of lecithin (anionic ingredient), as a lipophilic surfactant, in the dispersed phase and of the chitosan, as a hydrophilic suspending agent, in the continuous aqueous phase.
Lecithin is a natural surfactant composed of a mixture of various phospholipids. The mayor compound is phosphatidylcholine (phospholipid of a neutral character) and the secondary compounds are phosphatidylethanolamine, phosphatidylserine and phosphatidic acid (phospholipids with a negative charge). Presently, there are several types of lecithin available in the market. They differ in their origin and in their phosphatidylcholine content.
Chitosan is a natural polymer obtained by a deacetatilation process of the chitin (compound extracted from the crustacean shells). Chitosan is an aminopolysaccharide and has a positive charge. Presently, there are several types of chitosan available in the market. They differ in their molecular weight, deacetilation degree and the type of salt or acid form.
The colloidal systems covered in this patent are characterized because they contain lecithin and chitosan in their composition and they have a positive charge and an improved stability. Other ingredients will be specific of the type of system i.e. an oil, in the case of the submicron emulsions; an oil and a hydrophobic polymer, in the case of the nanocapsules, and a hydrophobic polymer in the case of the nanoparticles. Drugs, proteins and other bioactive compounds of interest in medicine and cosmetics can be incorporated in these systems.
2 i 5881 Consequently, the application of these systems could be extended to the fields of medicine and cosmetics.
A important draw back of the colloidal carriers is their unstability following in vivo administration and also during storage. It is well known that the majority of the colloidal carriers have a negative surface charge and, because of this fact, they interact with the cationic biologic compounds upon in vivo administration, thus leading to the coalesce and destruction of the system. Difficulties in the freeze-drying process, more specifically problems in the reconstitution of the freeze-dried systems, represent another important limitation for the correct exploitation of the colloidal systems specially the nanocapsules and submicron emulsions. As a Consequence, these systems have to be stored as a suspension liquid form, a situation that normally leads to the destruction of the systems in a few months. The novel systems presented in this patent have a positive charge ad an improved stability upon contact with biological rations and during storage. Consequently, these systems overcome the limitations mentioned above.
There are in the literature an important number of publications and patents describing procedures to produce colloidal systems such as nanoparticles, nanocapsules and submicron emulsions. Therefore, the production of these systems is not the object of the present invention. The object is, however, the incorporation in such colloidal systems of two specific ingredients: lecithin and chitosan. The preparation of these systems involves the use of two phases: an oily phase that is dispersed in an aqueous phase. Both phases normally contain surfactants. The most common surfactant introduced in the oily phase is lecithin. Lecithins are natural compounds that contain phosphatidylcholine and other phospholipids of negative charge. Consequently, colloidal systems containing lecithin have a more or less important negative surface charge. This negative charge normally leads to the destruction of the system, mainly upon contact with biological canons. This limitation inherent to most of the colloidal systems has been recently overcome by using lipophilic surfactants with a positive charge.
These positive surfactants are introduced in the dispersed oily phase (S.
Benita, oil-in water emulsion of positively charged particles WO 93/18852).
The present invention describes a new approach to provide the colloidal particles of a positive charge. This approach is based on the use of the cationic polyssacharide, chitosan, that is dissolved in the continuous aqueous phase and a lipid anionic surfactant, such as lecithin, that is introduced in the oily dispersed, phase. The positively charged chitosan molecules interact with the negatively charged phospholipids, thus forming a film at the interface of the colloidal system. The interaction process of chitosan with phospholipids was previously described as a way to stabilize emulsions (no submicron emulsions) ( P. Paldt, D. Berger~rtalcl, P.M. Claesson, Stabilization by chitosan of soybea» oil ernulsionr coated with phospholi~id and glycolic acid, Colloids Surfaces A: Physicoclzern. E»g. Aspects 71, 187-195, 1993) and liposomes (I. He»rikse», G. Smistad and J. Karlsen, Interactions between liposomes and chitosan, Int. J. Pharrn., 101, 227-236, 1994). Nevertheless, no reference concerning the application of such interaction (chitosan-phospholipid) to the stabilization of submicron emulsions, nanocapsules and nanoparticles has been found. On the other hand, it is important to mention that the approaches described until now for the freeze-drying of colloidal systems, such as nanocapsules and submicron emulsions, are based on the use of enormous amounts of sugars (R.J. Gautier and R.S. Levinson, Lyophilized emulsion compositions and method, youth Africa patent No. 864032) whereas the freeze drying of the nanocapsules covered in this invention require the use of relatively low amounts of sugars (less than 10010).
More particularly, the present invention provides a process for the preparation of pharmaceutical and cosmetic compositions in the form of colloidal particles of a size less than 1 pm suitable for the delivery of active comprising the steps of:
a. providing an organic solution comprising a negatively charged phospholipid and either a hydrophobic polymer or oil or both substances simultaneously, dissolved in an organic solvent, b. providing an aqueous solution of cationic aminopolysacharide selected from the group of chitin and chitosan, c. combining said organic and aqueous solutions to obtain a final aqueous medium, so as to simultaneously and spontaneously form and coat said colloidal particles with a film which is the ionic reaction product of said phospholipid and aminopolysacharide, and to provide said particles with a positive surface charge, wherein at least one of said solutions contains said active compounds.
The systems covered in this patent, characterized by the formation of a polysaccharide-lipid complex at the interface, have some relevant advantages: (1) The systems can be stared in a suspension liquid form for extended periods of time, (2) the nanocapsules based on this approach can be freeze dried and the resultant dry product reconstituted upon addition of water (3) the chitosan-coated nanocapsules herewith described are more stable in the presence of biological rations than conventional uncoated nanocapsules, (4) the systems have a positive electrical surface charge that enables their interaction with negatively charged biological surfaces.
The present invention describes novel systems of interest in therapeutics and cosmetics.
These systems can be presented in a liquid form of variable viscosity or in a semi-solid (cream) 3a or solid form (freeze-dried powder).
2195~~1 The dispersed phase of the system consists either of a polymer or an oil or both substances simultaneously. The specific ingredient of this dispersed phase is a negatively charged phospholipid. This phase can contain as well a variable amount of an active ingredient. The oils can be chosen among vegetable oils or semisynthetic polyoxyethylenated oils (Migliol~, Labrafil~, Labrafac~...) of various H.L.B. (hydrophilia lipophilia balance) values. The polymer can be any hydrophobic polymer which is adequate for pharmaceutical or cosmetic use. The proportion of the hydrophobic polymer with respect to the oily phase can vary from 0% (submicron emulsions) up to 100% (nanoparticles). Intermediate proportions lead to the formation of nanocapsules in which the oil is in the polymer forming a reservoir system.
The specific ingredient of the external aqueous phase is chitosan. 1~or freeze drying purposes some cryoprotective agents such as dextran and glucose need to be added to this external phase. This phase can incorporate as well ingredients to provide a certain density or viscosity to the preparation, bacteriostatic agents for the prevention of contamination and other hydrophilic agents.
These systems can be formulated in different ways in order to incorporate in their structure one or more active ingredients of a hydrophilic or lipophilic character. Active ingredient is the ingredient for which the formulation is destined; in other words, the ingredient which will have an effect following its administration to an organism (humans or animals).
The corresponding effect can be curing, minimizing or preventing a disease (drugs, vitamins, vaccines...) or improving the physical appearance and aesthetics (e.g... skin hydration...) and other.
Cyclosporin A, an immunossupressive peptide, indomethacin (anti-inflammatory drug) metipranolol (beta-blocker) and tiopental (hypnotic agent) are examples of drugs which have been successfully associated to the colloidal systems described in this patent.
A common feature to the systems described in this patent is the colloidal nature, which means that their size is lower that ly~m. Tables 1 and 2 show the mean particle size of the nanocapsules, submicron emulsions and nanoparticles containing the oil Migliol~ 840 and various amounts of polyepsiloncaprolactone, soybean lecithin and dextran.
A important draw back of the colloidal carriers is their unstability following in vivo administration and also during storage. It is well known that the majority of the colloidal carriers have a negative surface charge and, because of this fact, they interact with the cationic biologic compounds upon in vivo administration, thus leading to the coalesce and destruction of the system. Difficulties in the freeze-drying process, more specifically problems in the reconstitution of the freeze-dried systems, represent another important limitation for the correct exploitation of the colloidal systems specially the nanocapsules and submicron emulsions. As a Consequence, these systems have to be stored as a suspension liquid form, a situation that normally leads to the destruction of the systems in a few months. The novel systems presented in this patent have a positive charge ad an improved stability upon contact with biological rations and during storage. Consequently, these systems overcome the limitations mentioned above.
There are in the literature an important number of publications and patents describing procedures to produce colloidal systems such as nanoparticles, nanocapsules and submicron emulsions. Therefore, the production of these systems is not the object of the present invention. The object is, however, the incorporation in such colloidal systems of two specific ingredients: lecithin and chitosan. The preparation of these systems involves the use of two phases: an oily phase that is dispersed in an aqueous phase. Both phases normally contain surfactants. The most common surfactant introduced in the oily phase is lecithin. Lecithins are natural compounds that contain phosphatidylcholine and other phospholipids of negative charge. Consequently, colloidal systems containing lecithin have a more or less important negative surface charge. This negative charge normally leads to the destruction of the system, mainly upon contact with biological canons. This limitation inherent to most of the colloidal systems has been recently overcome by using lipophilic surfactants with a positive charge.
These positive surfactants are introduced in the dispersed oily phase (S.
Benita, oil-in water emulsion of positively charged particles WO 93/18852).
The present invention describes a new approach to provide the colloidal particles of a positive charge. This approach is based on the use of the cationic polyssacharide, chitosan, that is dissolved in the continuous aqueous phase and a lipid anionic surfactant, such as lecithin, that is introduced in the oily dispersed, phase. The positively charged chitosan molecules interact with the negatively charged phospholipids, thus forming a film at the interface of the colloidal system. The interaction process of chitosan with phospholipids was previously described as a way to stabilize emulsions (no submicron emulsions) ( P. Paldt, D. Berger~rtalcl, P.M. Claesson, Stabilization by chitosan of soybea» oil ernulsionr coated with phospholi~id and glycolic acid, Colloids Surfaces A: Physicoclzern. E»g. Aspects 71, 187-195, 1993) and liposomes (I. He»rikse», G. Smistad and J. Karlsen, Interactions between liposomes and chitosan, Int. J. Pharrn., 101, 227-236, 1994). Nevertheless, no reference concerning the application of such interaction (chitosan-phospholipid) to the stabilization of submicron emulsions, nanocapsules and nanoparticles has been found. On the other hand, it is important to mention that the approaches described until now for the freeze-drying of colloidal systems, such as nanocapsules and submicron emulsions, are based on the use of enormous amounts of sugars (R.J. Gautier and R.S. Levinson, Lyophilized emulsion compositions and method, youth Africa patent No. 864032) whereas the freeze drying of the nanocapsules covered in this invention require the use of relatively low amounts of sugars (less than 10010).
More particularly, the present invention provides a process for the preparation of pharmaceutical and cosmetic compositions in the form of colloidal particles of a size less than 1 pm suitable for the delivery of active comprising the steps of:
a. providing an organic solution comprising a negatively charged phospholipid and either a hydrophobic polymer or oil or both substances simultaneously, dissolved in an organic solvent, b. providing an aqueous solution of cationic aminopolysacharide selected from the group of chitin and chitosan, c. combining said organic and aqueous solutions to obtain a final aqueous medium, so as to simultaneously and spontaneously form and coat said colloidal particles with a film which is the ionic reaction product of said phospholipid and aminopolysacharide, and to provide said particles with a positive surface charge, wherein at least one of said solutions contains said active compounds.
The systems covered in this patent, characterized by the formation of a polysaccharide-lipid complex at the interface, have some relevant advantages: (1) The systems can be stared in a suspension liquid form for extended periods of time, (2) the nanocapsules based on this approach can be freeze dried and the resultant dry product reconstituted upon addition of water (3) the chitosan-coated nanocapsules herewith described are more stable in the presence of biological rations than conventional uncoated nanocapsules, (4) the systems have a positive electrical surface charge that enables their interaction with negatively charged biological surfaces.
The present invention describes novel systems of interest in therapeutics and cosmetics.
These systems can be presented in a liquid form of variable viscosity or in a semi-solid (cream) 3a or solid form (freeze-dried powder).
2195~~1 The dispersed phase of the system consists either of a polymer or an oil or both substances simultaneously. The specific ingredient of this dispersed phase is a negatively charged phospholipid. This phase can contain as well a variable amount of an active ingredient. The oils can be chosen among vegetable oils or semisynthetic polyoxyethylenated oils (Migliol~, Labrafil~, Labrafac~...) of various H.L.B. (hydrophilia lipophilia balance) values. The polymer can be any hydrophobic polymer which is adequate for pharmaceutical or cosmetic use. The proportion of the hydrophobic polymer with respect to the oily phase can vary from 0% (submicron emulsions) up to 100% (nanoparticles). Intermediate proportions lead to the formation of nanocapsules in which the oil is in the polymer forming a reservoir system.
The specific ingredient of the external aqueous phase is chitosan. 1~or freeze drying purposes some cryoprotective agents such as dextran and glucose need to be added to this external phase. This phase can incorporate as well ingredients to provide a certain density or viscosity to the preparation, bacteriostatic agents for the prevention of contamination and other hydrophilic agents.
These systems can be formulated in different ways in order to incorporate in their structure one or more active ingredients of a hydrophilic or lipophilic character. Active ingredient is the ingredient for which the formulation is destined; in other words, the ingredient which will have an effect following its administration to an organism (humans or animals).
The corresponding effect can be curing, minimizing or preventing a disease (drugs, vitamins, vaccines...) or improving the physical appearance and aesthetics (e.g... skin hydration...) and other.
Cyclosporin A, an immunossupressive peptide, indomethacin (anti-inflammatory drug) metipranolol (beta-blocker) and tiopental (hypnotic agent) are examples of drugs which have been successfully associated to the colloidal systems described in this patent.
A common feature to the systems described in this patent is the colloidal nature, which means that their size is lower that ly~m. Tables 1 and 2 show the mean particle size of the nanocapsules, submicron emulsions and nanoparticles containing the oil Migliol~ 840 and various amounts of polyepsiloncaprolactone, soybean lecithin and dextran.
219~~81 As mentioned above, a relevant property of the systems described here is their positive electrical charge. This positive charge promotes the interaction of the systems with the negatively charged mucosa and epithelia and also improves their stability in the presence of biological cations. As shown in table 3 the zeta potential of the systems varies between +30 and +60 mV, being these values dependent on the molecular weight of chitosan.
The inner structure of the systems described here is variable and dependent upon the composition of the system. As indicated before, the composition of the systems can vary substantially, the common ingredients being lecithin and chitosan or their derivatives. Two main inner structures can be described: a reservoir system consisting of an oily core surrounded or not by a polymer wall and a matrice system consisting of solid particles containing none or little amounts of oil entrapped.
The redispersability of the colloidal systems upon freeze-drying is a major advantage of the systems covered in this patent. Tables 3 and 4 show the particle size of the nanocapsules before and after freeze-drying.
The procedure described in this invention leads to the formation of novel systems for pharmaceutical or cosmetic applications. In addition, these systems could be administered by various routes: topical, oral, nasal, pulmonary, vaginal and subcutaneous. The specific ingredients, chitosan and lecithin, provide to these systems a positive electrical charge and an improved stability, not only during storage but also upon freeze-drying and further rehydration.
The inner structure of the systems described here is variable and dependent upon the composition of the system. As indicated before, the composition of the systems can vary substantially, the common ingredients being lecithin and chitosan or their derivatives. Two main inner structures can be described: a reservoir system consisting of an oily core surrounded or not by a polymer wall and a matrice system consisting of solid particles containing none or little amounts of oil entrapped.
The redispersability of the colloidal systems upon freeze-drying is a major advantage of the systems covered in this patent. Tables 3 and 4 show the particle size of the nanocapsules before and after freeze-drying.
The procedure described in this invention leads to the formation of novel systems for pharmaceutical or cosmetic applications. In addition, these systems could be administered by various routes: topical, oral, nasal, pulmonary, vaginal and subcutaneous. The specific ingredients, chitosan and lecithin, provide to these systems a positive electrical charge and an improved stability, not only during storage but also upon freeze-drying and further rehydration.
21 ~~~~~1 Table 1: Particle size of the poly(e-caprolactone) (PECL) nanocapsules containing Migliol 840 and a fixed concentration of chitosan (Seacure 123, 0.2% ) % Lecithin % Dextran % PECL (w/v) (w/v) (w/v) 0,5 1 340 t 23 361 22 353 t 21 0,5 2 278 t 43 324 28 292 t 38 1,5 I 314 t 19 341 t 18 346 t 20 1,5 2 284 t 12 321 t 10 339 t 13 21 °~~~' 1 Table 2: Particle size of the poly(e-caprolactone) (PECL) nanoparticles prepared with a fixed concentration of chitosan (Seacure 223, 0.2% ) % Lecithin % Dextran % PCL (w/v) (w/v) (w/v) 0,5 1 290 t 16 308 t 15 0,5 2 286 t 12 296 t 20 1 1 330 t 15 330 t 2 1 2 299 t 16 317 t 10 1,5 1 337 10 355 t 19 1,5 2 326 t 18 332 t 12 Table 3: Zeta potential of the poly(e-caprolactone) (PECL) nanocapsules and submicron emulsions containing Migliol ~ 840 and a fixed concentration of chitosan (Seacure 320, 0.2%).
% Lecithin Zeta Potential (w/v) (mV ) -Submicron emulsions Nanocapsules PECL 1% PECL 2 %
0,5 +522 +60 1 +601 1 1 + 601 1 + 61 t 1 + 6010.07 1,5 + 5910.3 + 59 2 + 61 10.4 21 ~ ~~~~1 "'~ Table 4: Particle size of the poly(e-caprolactone) (PECL) nanocapsules containing Migliol 840 and a fixed concentration of chitosan (Seacure 223 viscosity 100 cps and Seacure 320 viscosity 680 cps, 0.2% ). Final concentration of PECL and lecithin in the suspension: 1 % and 0.5% respectively.
Chitosan % Dextran Particle size (nm) viscosity (p/v) (cps) Before freeze-dryingAfter freeze-drying 1~ 1 459 t 23 487119 100 2 472 t 8 462 t 19 680 1 443 t 30 475 t 30 680 2 461 t 13 SOS t 16 Example 1:
-Preparation of a formulation of nanocapsules containing PECL and Migliol ~
840.
The nanocapsules were prepared using the following ingredients (%, wlw):
Migliol~ 840 oil...................Ø5 Soybean lecithin.....................1.0 polyepsiloncaprolactone.........1.0 Dextran...................................1.0 Chitosan.................................Ø2 Water...........................up to 100%
Chitosan and dextran were dissolved in an acidic aqueous solution (acetic acid O.OSM, pH 5.0). The oil Migliol~ 840, the surfactant soybean lecithin and the polymer poly( E
caprolactone) were dissolved in 25 ml of acetone. The acetonic.solution was then added, upon ' 21 °5~'~ 1 magnetic agitation, to an aqueous solution. Three min later the system was transferred to a rotavapor for the elimination of the acetone. The size and zeta potential of the nanocapsules were: 385 nm and +45mV respectively.
Finally, glucose was dissolved in the aqueous suspending medium and the nanocapsules freeze-dried. The particle size and zeta potential of the nanocapsules was determined again upon freeze-drying and resuspension. Results were: 359 nm and +42mV.
Example 2:
--Preparation of a formulation of nanocapsules containing PECL and Migliol ~
840.
The nanocapsules were prepared as described in example 1 but containing different amounts of lecithin and oil::
Migliol~ 840 oil......................1.5 Soybean lecithin......................Ø5 polyepsioloncaprolactone.........1.0 Dextran.....................................1.0 Chitosan...................................Ø2 Water..............................up to 100%
The particle size and zeta potential of these nanocapsules were: 433 nm and +32 mV, respectively, before freeze-drying and 582 and +43 mV after freeze-drying.
% Lecithin Zeta Potential (w/v) (mV ) -Submicron emulsions Nanocapsules PECL 1% PECL 2 %
0,5 +522 +60 1 +601 1 1 + 601 1 + 61 t 1 + 6010.07 1,5 + 5910.3 + 59 2 + 61 10.4 21 ~ ~~~~1 "'~ Table 4: Particle size of the poly(e-caprolactone) (PECL) nanocapsules containing Migliol 840 and a fixed concentration of chitosan (Seacure 223 viscosity 100 cps and Seacure 320 viscosity 680 cps, 0.2% ). Final concentration of PECL and lecithin in the suspension: 1 % and 0.5% respectively.
Chitosan % Dextran Particle size (nm) viscosity (p/v) (cps) Before freeze-dryingAfter freeze-drying 1~ 1 459 t 23 487119 100 2 472 t 8 462 t 19 680 1 443 t 30 475 t 30 680 2 461 t 13 SOS t 16 Example 1:
-Preparation of a formulation of nanocapsules containing PECL and Migliol ~
840.
The nanocapsules were prepared using the following ingredients (%, wlw):
Migliol~ 840 oil...................Ø5 Soybean lecithin.....................1.0 polyepsiloncaprolactone.........1.0 Dextran...................................1.0 Chitosan.................................Ø2 Water...........................up to 100%
Chitosan and dextran were dissolved in an acidic aqueous solution (acetic acid O.OSM, pH 5.0). The oil Migliol~ 840, the surfactant soybean lecithin and the polymer poly( E
caprolactone) were dissolved in 25 ml of acetone. The acetonic.solution was then added, upon ' 21 °5~'~ 1 magnetic agitation, to an aqueous solution. Three min later the system was transferred to a rotavapor for the elimination of the acetone. The size and zeta potential of the nanocapsules were: 385 nm and +45mV respectively.
Finally, glucose was dissolved in the aqueous suspending medium and the nanocapsules freeze-dried. The particle size and zeta potential of the nanocapsules was determined again upon freeze-drying and resuspension. Results were: 359 nm and +42mV.
Example 2:
--Preparation of a formulation of nanocapsules containing PECL and Migliol ~
840.
The nanocapsules were prepared as described in example 1 but containing different amounts of lecithin and oil::
Migliol~ 840 oil......................1.5 Soybean lecithin......................Ø5 polyepsioloncaprolactone.........1.0 Dextran.....................................1.0 Chitosan...................................Ø2 Water..............................up to 100%
The particle size and zeta potential of these nanocapsules were: 433 nm and +32 mV, respectively, before freeze-drying and 582 and +43 mV after freeze-drying.
21~5~~1 Example 3:
--Preparation of a formulation of a submicron emulsion containing Migliol ~
840.
The emulsion was prepared as described in example 1 but without the polymer PECL:
Migliol~ 840 oil....................1.5 Soybean lecithin......................Ø5 Dextran..................................1.0 Chitosan...............................Ø2 Water...........................upto 100%
The results of particle size and zeta potential were: 463 nm and +42 mV, respectively.
--Preparation of a formulation of a submicron emulsion containing Migliol ~
840.
The emulsion was prepared as described in example 1 but without the polymer PECL:
Migliol~ 840 oil....................1.5 Soybean lecithin......................Ø5 Dextran..................................1.0 Chitosan...............................Ø2 Water...........................upto 100%
The results of particle size and zeta potential were: 463 nm and +42 mV, respectively.
Claims (12)
1. Process for the preparation of pharmaceutical and cosmetic compositions in the form of colloidal particles of a size less than 1µm suitable for the delivery of active compounds comprising the steps of:
a. providing an organic solution comprising a negatively charged phospholipid and either a hydrophobic polymer or oil or both substances simultaneously, dissolved in an organic solvent, b. providing an aqueous solution of cationic aminopolysacharide selected from the group of chitin and chitosan, c. combining said organic and aqueous solutions to obtain a final aqueous medium, so as to simultaneously and spontaneously form and coat said colloidal particles with a film which is the ionic reaction product of said phospholipid and aminopolysacharide, and to provide said particles with a positive surface charge, wherein at least one of said solutions contains said active compounds.
a. providing an organic solution comprising a negatively charged phospholipid and either a hydrophobic polymer or oil or both substances simultaneously, dissolved in an organic solvent, b. providing an aqueous solution of cationic aminopolysacharide selected from the group of chitin and chitosan, c. combining said organic and aqueous solutions to obtain a final aqueous medium, so as to simultaneously and spontaneously form and coat said colloidal particles with a film which is the ionic reaction product of said phospholipid and aminopolysacharide, and to provide said particles with a positive surface charge, wherein at least one of said solutions contains said active compounds.
2. Process according to claim 1, characterized in that said phospholipid is selected from the groups of lecithins and derivatives thereof.
3. Process according to claim 1 or 2, characterized in that the percentage of the aminopolysaccharide in the final aqueous medium can be up to 2% by weight/weight.
4. Process according to claim 1 and 2, characterized in that the percentage of the aminopolysaccharide in the final aqueous medium is between 0.05 and 0.5% by weight/weight.
5. Process according to any one of claims 1 to 4, characterized in that the percentage of the phospholipid in the final aqueous medium can be up to 5% by weight/weight.
6. Process according to any one of claims 1 to 4, characterized in that the percentage of the phospholipid in the final aqueous medium is between 0.2 and 1 % by weight/weight.
7. Process according to any one of claim 1 to 6, characterized in that the colloidal particles are nanodroplets which are formed upon the incorporation of a vegetable or semisynthetic oil, dissolved in the organic phase, the oil being in an amount up to 1% by weight/weight with respect to the external aqueous medium.
8. Process according to any one of claims 1 to 6, characterized in that the colloidal particles are nanocapsules which are formed upon the incorporation of a vegetable or semisynthetic oil and a polyester dissolved in the organic phase, the oil and the polyester being in variable proportions up to 1% by weight/weight and 4% by weight/weight respectively.
9. Process according to any one of claims 1 to 6, characterized in that the colloidal particles are nanoparticles which are formed upon the incorporation of a polyester, dissolved in the organic phase, the polyester being in variable proportions up to 4% by weight/weight.
10. Process according to claim 6, characterized in that the compositions includes complementary ingredients selected form the group consisting of dextran at 1 to 2% by weight/weight and glucose at 5% by weight/weight, to allow the freeze-drying of the nanocapsules and further resuspension in water.
11. Process according to any one of claims 1 to 10, characterized in that said active compounds are selected from the group consisting of indomethacin, metipranolol, diazepam and cyclosporine A.
12. Process according to claim 1, characterized in that the compositions include ingredients which are non-toxic and compatible with their application by topical, oral, nasal, vaginal and pulmonary routes of administration, said particles having a positive charge that facilitates their interaction with mucosas and epithelia.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES09501035A ES2093562B1 (en) | 1995-05-26 | 1995-05-26 | STABILIZATION OF COLLOID SYSTEMS THROUGH FORMATION OF LIPIDO-POLISACARIDO IONIC COMPLEXES. |
ESP9501035 | 1995-05-26 | ||
PCT/ES1996/000116 WO1996037232A1 (en) | 1995-05-26 | 1996-05-24 | Stabilization of colloidal systems by the formation of ionic lipid-polysaccharide complexes |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2195881A1 CA2195881A1 (en) | 1996-11-28 |
CA2195881C true CA2195881C (en) | 2006-09-12 |
Family
ID=8290513
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002195881A Expired - Fee Related CA2195881C (en) | 1995-05-26 | 1996-05-24 | Stabilization of colloidal systems through the formation of lipid-polysaccharide complexes |
Country Status (9)
Country | Link |
---|---|
US (1) | US5843509A (en) |
EP (1) | EP0771566B1 (en) |
AT (1) | ATE330636T1 (en) |
CA (1) | CA2195881C (en) |
DE (1) | DE69634927T2 (en) |
DK (1) | DK0771566T3 (en) |
ES (1) | ES2093562B1 (en) |
PT (1) | PT771566E (en) |
WO (1) | WO1996037232A1 (en) |
Families Citing this family (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5766629A (en) | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
US5993856A (en) * | 1997-01-24 | 1999-11-30 | Femmepharma | Pharmaceutical preparations and methods for their administration |
US6416778B1 (en) | 1997-01-24 | 2002-07-09 | Femmepharma | Pharmaceutical preparations and methods for their regional administration |
FR2760641B1 (en) * | 1997-03-13 | 2000-08-18 | Oreal | STABLE OIL-IN-WATER EMULSION, MANUFACTURING METHOD THEREOF AND USE THEREOF IN THE COSMETIC AND DERMATOLOGICAL FIELDS |
DE19733625A1 (en) * | 1997-07-28 | 1999-02-04 | Lancaster Group Gmbh | Decorative cosmetic O / W emulsion |
KR19990058599A (en) * | 1997-12-30 | 1999-07-15 | 손경식 | Cosmetic composition containing a double capsule |
DE19826503A1 (en) * | 1998-06-13 | 1999-12-16 | Beiersdorf Ag | Cosmetic and dermatological preparations containing chitosan and phospholipids |
ATE293895T1 (en) * | 1999-10-29 | 2005-05-15 | Hunza Di Pistolesi Elvira E C | FIBROUS LIPO NUTRITIONAL COMPLEXES AND COMPOSITIONS CONTAINING SAME |
FR2801811B1 (en) * | 1999-12-06 | 2002-05-03 | Gerard Habar | PROCESS FOR THE MANUFACTURE OF MICROCAPSULES CARRYING CATIONIC CHARGES |
EP1257353B1 (en) * | 2000-02-23 | 2004-11-03 | Henkel Kommanditgesellschaft auf Aktien | Washing or cleaning composition having components in form microcapsules and/or nanocapsules |
US6761901B1 (en) | 2000-05-02 | 2004-07-13 | Enzrel Inc. | Liposome drug delivery |
US6689760B1 (en) | 2000-07-10 | 2004-02-10 | Enzrel Inc. | Anti-mycobacterial compositions |
US6455073B1 (en) | 2000-07-10 | 2002-09-24 | Enzrel, Inc. | Covalent microparticle-drug conjugates for biological targeting |
US7371456B2 (en) | 2000-10-02 | 2008-05-13 | Kimberly-Clark Worldwide, Inc. | Nanoparticle based inks and methods of making the same |
US20030129223A1 (en) * | 2000-10-11 | 2003-07-10 | Targesome, Inc. | Targeted multivalent macromolecules |
US20030133972A1 (en) * | 2000-10-11 | 2003-07-17 | Targesome, Inc. | Targeted multivalent macromolecules |
AU2002245629A1 (en) * | 2001-03-08 | 2002-09-24 | Targesome, Inc. | Stabilized therapeutic and imaging agents |
US6673263B2 (en) | 2001-07-26 | 2004-01-06 | Ppg Industries Ohio, Inc. | Compositions incorporating chitosan for paint detackification |
US20040000329A1 (en) * | 2001-07-26 | 2004-01-01 | Albu Michael L. | Compositions and methods for paint overspray removal processes |
EP1443905A4 (en) * | 2001-10-03 | 2010-06-23 | Univ Johns Hopkins | Compositions for oral gene therapy and methods of using same |
MXPA04006017A (en) * | 2001-12-20 | 2005-06-08 | Femmepharma Inc | Vaginal delivery of drugs. |
AU2003210477A1 (en) * | 2002-01-09 | 2003-07-30 | Enzrel, Inc. | Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds |
CA2376993A1 (en) * | 2002-03-15 | 2003-09-15 | Go Young Moon | Chitosan / anionic surfactant complex membrane |
ES2197836B1 (en) * | 2002-06-28 | 2005-05-01 | Consejo Sup. Investig. Cientificas | PROCEDURE FOR THE PREPARATION OF NANO-EMULSIONS OF WATER TYPE IN OIL (W / O) BY METHODS OF EMULSIFICATION OF CONDENSATION. |
US8409618B2 (en) | 2002-12-20 | 2013-04-02 | Kimberly-Clark Worldwide, Inc. | Odor-reducing quinone compounds |
US7666410B2 (en) | 2002-12-20 | 2010-02-23 | Kimberly-Clark Worldwide, Inc. | Delivery system for functional compounds |
US6780896B2 (en) * | 2002-12-20 | 2004-08-24 | Kimberly-Clark Worldwide, Inc. | Stabilized photoinitiators and applications thereof |
EP1578421A4 (en) * | 2003-01-02 | 2009-04-22 | Femmepharma Holding Co Inc | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
US9173836B2 (en) | 2003-01-02 | 2015-11-03 | FemmeParma Holding Company, Inc. | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
EP1656192B1 (en) * | 2003-08-20 | 2015-08-26 | Merck Patent GmbH | Methods for extraction and concentration of hydrophilic compounds from hydrophobic liquid matrices |
US7754197B2 (en) | 2003-10-16 | 2010-07-13 | Kimberly-Clark Worldwide, Inc. | Method for reducing odor using coordinated polydentate compounds |
US7413550B2 (en) | 2003-10-16 | 2008-08-19 | Kimberly-Clark Worldwide, Inc. | Visual indicating device for bad breath |
US7794737B2 (en) | 2003-10-16 | 2010-09-14 | Kimberly-Clark Worldwide, Inc. | Odor absorbing extrudates |
US7879350B2 (en) | 2003-10-16 | 2011-02-01 | Kimberly-Clark Worldwide, Inc. | Method for reducing odor using colloidal nanoparticles |
US7678367B2 (en) | 2003-10-16 | 2010-03-16 | Kimberly-Clark Worldwide, Inc. | Method for reducing odor using metal-modified particles |
US7488520B2 (en) | 2003-10-16 | 2009-02-10 | Kimberly-Clark Worldwide, Inc. | High surface area material blends for odor reduction, articles utilizing such blends and methods of using same |
US7837663B2 (en) | 2003-10-16 | 2010-11-23 | Kimberly-Clark Worldwide, Inc. | Odor controlling article including a visual indicating device for monitoring odor absorption |
CA2541445A1 (en) * | 2003-10-31 | 2005-05-12 | Teva Pharmaceutical Industries Ltd. | Nanoparticles for drug delivery |
KR100638041B1 (en) * | 2003-12-24 | 2006-10-23 | 주식회사 삼양사 | A nanoparticle composition of a water-soluble drug for oral administration and a preparation method thereof |
US8562505B2 (en) | 2004-02-20 | 2013-10-22 | The Children's Hospital Of Philadelphia | Uniform field magnetization and targeting of therapeutic formulations |
US7846201B2 (en) * | 2004-02-20 | 2010-12-07 | The Children's Hospital Of Philadelphia | Magnetically-driven biodegradable gene delivery nanoparticles formulated with surface-attached polycationic complex |
US9028829B2 (en) * | 2004-02-20 | 2015-05-12 | The Children's Hospital Of Philadelphia | Uniform field magnetization and targeting of therapeutic formulations |
US20060003956A1 (en) * | 2004-03-03 | 2006-01-05 | Casadome David O | Materials and methods for the derepression of the E-cadherin promoter |
US7901707B2 (en) * | 2004-03-15 | 2011-03-08 | Christine Allen | Biodegradable biocompatible implant and method of manufacturing same |
CN1311867C (en) * | 2004-09-27 | 2007-04-25 | 侯新朴 | Nerve growth factor (NGF) liposome |
ES2259914B1 (en) * | 2005-03-14 | 2007-06-16 | Advanced In Vitro Cell Technologies, S.L. | NANOPARTICULAS OF QUITOSANO AND POLYETHYLENE GLYCOL AS A SYSTEM OF ADMINISTRATION OF BIOLOGICALLY ACTIVE MOLECULES. |
EP1834635B1 (en) * | 2006-03-13 | 2011-07-06 | Advanced in Vitro Cell Technologies, S.L. | Stable nanocapsule systems for the administration of active molecules |
US7977103B2 (en) | 2006-04-20 | 2011-07-12 | Kimberly-Clark Worldwide, Inc. | Method for detecting the onset of ovulation |
CA2674078C (en) * | 2006-12-26 | 2012-03-20 | Femmepharma Holding Company, Inc. | Topical administration of danazol |
US8703204B2 (en) | 2007-05-03 | 2014-04-22 | Bend Research, Inc. | Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and anon-ionizable polymer |
WO2008135828A2 (en) | 2007-05-03 | 2008-11-13 | Pfizer Products Inc. | Nanoparticles comprising a drug, ethylcellulose, and a bile salt |
WO2008149230A2 (en) | 2007-06-04 | 2008-12-11 | Pfizer Products Inc. | Nanoparticles comprising drug, a non-ionizable cellulosic polymer and tocopheryl polyethylene glycol succinate |
WO2008149192A2 (en) | 2007-06-04 | 2008-12-11 | Pfizer Products Inc. | Nanoparticles comprising a non-ionizable cellulosic polymer and an amphiphilic non-ionizable block copolymer |
EP2240162A4 (en) | 2007-12-06 | 2013-10-09 | Bend Res Inc | Nanoparticles comprising a non-ionizable polymer and an amine-functionalized methacrylate copolymer |
EP2231169B1 (en) | 2007-12-06 | 2016-05-04 | Bend Research, Inc. | Pharmaceutical compositions comprising nanoparticles and a resuspending material |
IL188647A0 (en) | 2008-01-08 | 2008-11-03 | Orina Gribova | Adaptable structured drug and supplements administration system (for oral and/or transdermal applications) |
US8778400B2 (en) * | 2008-04-21 | 2014-07-15 | University Of South Australia | Nanoparticle-stabilized capsule formulation for treatment of inflammation |
US9207242B2 (en) | 2008-10-09 | 2015-12-08 | The University Of Hong Kong | Cadherin-17 as diagnostic marker and therapeutic target for liver cancer |
EP2266546A1 (en) | 2009-06-08 | 2010-12-29 | Advancell Advanced in Vitro Cell Technologies,S.A. | Process for the preparation of colloidal systems for the delivery of active compounds |
US20110003000A1 (en) * | 2009-07-06 | 2011-01-06 | Femmepharma Holding Company, Inc. | Transvaginal Delivery of Drugs |
BR112012000379A2 (en) | 2009-07-09 | 2016-03-29 | Oshadi Drug Administration Ltd | carrier matrix compositions, methods and uses |
EP2361509A1 (en) | 2010-02-15 | 2011-08-31 | Nestec S.A. | Liquid-filled protein-phosphatidic acid capsule dispersions |
EP2364600A1 (en) | 2010-02-18 | 2011-09-14 | Nestec S.A. | Liquid-filled chitosan-anionic liposoluble capsule dispsersions |
BRPI1002601E2 (en) * | 2010-06-01 | 2020-06-30 | Embrapa Pesquisa Agropecuaria | nanostructured composition for veterinary use for drug administration |
US9326980B2 (en) * | 2013-07-21 | 2016-05-03 | Kimia Zist Parsian (Kzp) | Method and system for synthesizing nanocarrier based long acting drug delivery system for buprenorphine |
US9351932B2 (en) * | 2014-07-21 | 2016-05-31 | Kimia Zist Parsian (Kzp) | Method and system for synthesizing nanocarrier based long acting drug delivery system for methadone |
PL229276B1 (en) | 2015-07-17 | 2018-06-29 | Univ Jagiellonski | Nanocapsule for transferring lipophile compound and method for producing it |
GB201522186D0 (en) | 2015-12-16 | 2016-01-27 | Singapore Health Services Pte Ltd And Nat University Of Singapore The | Treatment of fibrosis |
US20200129575A1 (en) | 2017-02-09 | 2020-04-30 | Universidade De Santiago De Compostela | Purified pollen particles and use thereof for administering nanosystems |
US11883401B2 (en) | 2019-01-08 | 2024-01-30 | Duke University | Compositions for the treatment of pathogenic- and/or chemical-induced lung injury and for the treatment of cancer and methods of using same |
WO2020152122A1 (en) | 2019-01-21 | 2020-07-30 | Singapore Health Services Pte. Ltd. | Treatment of hepatotoxicity |
GB201902419D0 (en) | 2019-02-22 | 2019-04-10 | Singapore Health Serv Pte Ltd | Treatment of kidney injury |
GB201906291D0 (en) | 2019-05-03 | 2019-06-19 | Singapore Health Serv Pte Ltd | Treatment and prevention of metabolic diseases |
JP2022531591A (en) | 2019-05-03 | 2022-07-07 | シンガポール・ヘルス・サービシーズ・ピーティーイー・リミテッド | Treatment and prevention of metabolic disorders |
GB202009292D0 (en) | 2020-06-18 | 2020-08-05 | Singapore Health Serv Pte Ltd | Treatment and prevention of disease caused by type IV collagen dysfunction |
GB202017244D0 (en) | 2020-10-30 | 2020-12-16 | Nat Univ Singapore | Methods to extend health-span and treat age-related diseases |
WO2023006765A1 (en) | 2021-07-26 | 2023-02-02 | Boehringer Ingelheim International Gmbh | Treatment and prevention of alcoholic liver disease |
WO2023111196A1 (en) | 2021-12-16 | 2023-06-22 | Singapore Health Services Pte. Ltd. | Treatment and prevention of glomerular disease |
GB202212077D0 (en) | 2022-08-18 | 2022-10-05 | Tribune Therapeutics Ab | Agents that inhibit ccn ligand-induced signalling for treating disease |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1243390B (en) * | 1990-11-22 | 1994-06-10 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF PARTICLES SUITABLE FOR THE CONTROLLED RELEASE OF PHARMACOLOGICALLY ACTIVE SUBSTANCES AND PROCEDURE FOR THEIR PREPARATION. |
IL101241A (en) * | 1992-03-16 | 1997-11-20 | Yissum Res Dev Co | Pharmaceutical or cosmetic composition comprising stabilized oil-in-water type emulsion as carrier |
-
1995
- 1995-05-26 ES ES09501035A patent/ES2093562B1/en not_active Expired - Fee Related
-
1996
- 1996-05-24 CA CA002195881A patent/CA2195881C/en not_active Expired - Fee Related
- 1996-05-24 WO PCT/ES1996/000116 patent/WO1996037232A1/en active IP Right Grant
- 1996-05-24 DE DE69634927T patent/DE69634927T2/en not_active Expired - Lifetime
- 1996-05-24 PT PT96914215T patent/PT771566E/en unknown
- 1996-05-24 AT AT96914215T patent/ATE330636T1/en not_active IP Right Cessation
- 1996-05-24 US US08/776,507 patent/US5843509A/en not_active Expired - Lifetime
- 1996-05-24 DK DK96914215T patent/DK0771566T3/en active
- 1996-05-24 EP EP96914215A patent/EP0771566B1/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
EP0771566B1 (en) | 2006-06-21 |
ES2093562A1 (en) | 1996-12-16 |
EP0771566A1 (en) | 1997-05-07 |
PT771566E (en) | 2006-08-31 |
WO1996037232A1 (en) | 1996-11-28 |
US5843509A (en) | 1998-12-01 |
DE69634927D1 (en) | 2005-08-18 |
CA2195881A1 (en) | 1996-11-28 |
ES2093562B1 (en) | 1997-07-01 |
ATE330636T1 (en) | 2006-07-15 |
DK0771566T3 (en) | 2006-10-23 |
DE69634927T2 (en) | 2008-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2195881C (en) | Stabilization of colloidal systems through the formation of lipid-polysaccharide complexes | |
US5174930A (en) | Process for the preparation of dispersible colloidal systems of amphiphilic lipids in the form of oligolamellar liposomes of submicron dimensions | |
US5049322A (en) | Process for the preparaton of dispersible colloidal systems of a substance in the form of nanocapsules | |
US5962015A (en) | Stabilized liposomes | |
KR100317751B1 (en) | Synthetic particulate vector and its manufacturing method | |
CA2358505C (en) | Novel hydrogel isolated cochleate formulations, process of preparation and their use for the delivery of biologically relevant molecules | |
Rajera et al. | Niosomes: a controlled and novel drug delivery system | |
Calvo et al. | Development of positively charged colloidal drug carriers: chitosan-coated polyester nanocapsules and submicron-emulsions | |
US5665379A (en) | Lipid particle forming matrix, preparation and use thereof | |
JP2958774B2 (en) | Improved preparation of amphotericin B liposomes | |
US4844904A (en) | Liposome composition | |
RU2216315C2 (en) | Method for preparing liposomes | |
JP3695754B2 (en) | Improvements related to pharmaceutical compositions | |
JP2002507966A (en) | Preparation of pharmaceutical composition | |
Jose et al. | Polymeric lipid hybrid nanoparticles: properties and therapeutic applications | |
GB2166107A (en) | Lipid spherule composition and process for its preparation | |
JP2006508126A (en) | Protein-stabilized liposome formulation of pharmaceutical formulation | |
KR102037354B1 (en) | Nano-lipid carrier for encapsulation of physiologically active substance and preparation method thereof | |
JP2855594B2 (en) | Lipid particle forming matrix and method for producing the same | |
EP1552820A1 (en) | Aqueous dispersion of nanocapsules with an oily core and method of preparing it | |
KR101405417B1 (en) | Manufacturing Method of Skin External Composition Controlled Transepidermal Absorption Using Phase Transition of Lysophospholipids based Colloid | |
Khopade et al. | Liposphere based lipoprotein-mimetic delivery system for 6-mercaptopurine | |
JPWO2003015753A1 (en) | Liposome preparation | |
CN1102565A (en) | Grease cosmetics containing amino acid and VA | |
Patil Abhishek et al. | NIOSOMES: A PROMISING DRUG DELIVERY CARRIER |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |
Effective date: 20130524 |