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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
  • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases or cochleates; Sponge phases

Definitions

• the present invention is within the field of encapsulating biologically active materials primarily in order to obtain a controlled, including sustained, release as well as increased uptake thereof as is desirable in many different technical fields, such as for instance to have a longer lasting or delayed effect of a pharmaceutically active material. More specifically the invention is based on a novel encapsulating or carrier material or system possessing a number of interesting features.
• a third type of carrier using lipids and lipid analogues is a microemulsion, which has recently been marketed as a carrier for cyclosporin. Furthermore, PCT/SE96/00893 can be referred to, which discloses the use of an L2 phase as a carrier for a cyclosporin.
• the carrier systems referred to above are generally based on fatty acid esters of glycerol.
• the present invention is, however, based on a new carrier system, viz. a certain class of fatty acid esters of diglycerol.
• fatty acids of polyglycerol have hitherto been used as functional additives in foods and in cosmetic formulations.
• the diglycerol esters upon which the present invention is based have never been disclosed or even suggested as carri- er materials. More specifically, the characteristics of those diglycerol esters which by themselves form lipid water phases have never been utilized for controlled release of biologically active agents.
• EP 0 455 391 discloses polyglycerol fatty acid esters for use e.g. in the pharmaceutical field.
• the preparations disclosed therein are granulated, i.e. solid, compositions and do not have all valuable properties possessed by the liquid or liquid crystalline composition according the present invention.
• EP 0 455 391 is not specifically directed to any diglycerol esters or any valuable properties thereof as compared to other polyglycerol esters.
• the present invention is based on the unexpec- ted finding that certain fatty acid esters of diglycerol are highly efficient in solubilizing or dispersing biologically active materials, both as such and in combination with polar liquids. More specifically the present invention is based on the finding that the diglycerol fatty acid esters defined herein can form liquid or liquid crystalline lipid phases of those types which were referred to above in the opening part of our description. Firstly, these phases can be used to protect a biologically active material, for example against degradation in the gastric region, or against oxidation and hydrolysis, e.g. during storage.
• the uptake of the biologically active material can be improved, particularly penetration through mucous layers and membranes, for instance in oral delivery or in topical delivery, a great advantage being that the systems are bioadhesive.
• Other advantageous properties to be mentioned are non-irritant and non-toxic properties, which seem to be dependent, at least to some extent, on the length (s) of the hydrocarbon chains.
• the previously known lipid phases can be accomplished in a simple way according to the present invention, viz. merely by varying the number or length of the hydrocarbon chains per molecule. In ot- her words the phase properties can be varied successively in a very easy and advantageous way so as to control and optimize the desired delivery of for instance a particular drug.
• phase properties it could be added that within the invention it is possible to accomplish diglycerol ester-water (or other polar liquid) phases ranging from the L ⁇ -type to the oil-continuous L2- type, the liquid crystalline phases cubic and reversed hexagonal phases lying therebetween. As a consequence thereof it is also possible, by a simple variation of the hydrocarbon chains, to adjust the composition of the system so as to be more or less close to any of these phase transitions. As an example of an interesting advantage in certain applications it could be mentioned that a composition or formulation just on the edge of, or adjacent to, a transition from lamellar to cubic phase represents fusion of cell membranes.
• micellar solutions can be formed in cases of diglycerol esters of the shortest members of the fatty acids referred to.
• the composition is an L2 phase containing especially diglycerol monoester of fatty acid and which when contacted with water, or other polar liquid, is transformed into a liquid crystalline phase.
• Such a contact with water (or polar liquid) can take place in the human or animal body or outside the same.
• the present invention relates to a controlled-release composition for a biologically active material, which composition is liquid or liquid crystalline and comprises at least one medium or long chain fat- ty acid ester of diglycerol as a carrier for said biologically active material, said biologically active material being dissolved or dispersed in said carrier.
• compositions claimed can be presented as follows.
• Especially preferable liquid or liquid crystalline compositions according to the invention are selected from the follwing groups: a lamellar liquid phase; a cubic liquid crystalline phase; a reversed hexagonal liquid crystalline phase; and an L2 phase.
• a lamellar liquid phase a lamellar liquid phase
• a cubic liquid crystalline phase a reversed hexagonal liquid crystalline phase
• an L2 phase an L2 phase.
• fatty acid ester of diglycerol as such as said carrier but to include into the composition also a polar liquid.
• water may often be a favourable polar liquid but also other polar liquids are useful in accordance with the invention as long as they have the above-mentioned ability of forming any of the previously known well-defined lipid phases with said fatty acid ester (s) of diglycerol.
• the polar liquid is selected from water, glycerol, ethylene glycol, propylene glycol, ethanol and mixtures thereof.
• the inventive idea is generally applicable to any medium or long chain fatty acid to be used in esterifying the diglycerol, the lower and upper limits as to the number of carbon atoms not being strictly rigid.
• the fatty acids to be used in the composition claimed, or rather in the diglycerol esters should be fatty acid(s) having in total 6-18 carbon atoms.
• one favourable group of fatty acids is the group of fatty acids comprising C 6 -C ⁇ -fatty acids, while another preferable group of fatty acids can be considered represented by the group of C ⁇ 6 -C ⁇ 8 -fatty acids.
• Said fatty acids can generally be saturated or un- saturated fatty acids.
• said acids are preferably selected among saturated fatty acids.
• saturated fatty acids are caprylic acid, capric acid, lauric acid and myristic acid.
• Ci 6 _ C ⁇ 8 -fatty acids are preferably selected among unsaturated fatty acids, preferable examples thereof being oleic acid, ricinoleic acid, linolic acid and linolenic acid.
• diglycerol esters are previously known per se, reference can be made to the prior art concerning the preparation of such esters. Generally, however, it can be said that the compounds in question can be prepared by molecular distillation, starting from diglycerol and free fatty acid(s) in appropriate proportions with regard to the desired degree of substitution. As a maximum the diglycerol molecule can be esterified with four fatty acid molecules, and as a minimum with one such molecule.
• the different esters have different boiling points, and therefore the distillation can be operated to the desired mixture or composition by varying the distillation tempe- rature correspondingly.
• Mono-, di-, tri- and tetra- esterified diglycerols can all be utilized in connection with the present invention, although the mono- and/or di- esters are generally preferred.
• An especially preferable embodiment is represented by an esterified diglycerol wherein the monoester is the major ingredient, i.e. present to more than 50% by weight, preferably more than 70% by weight, more preferably more than 80% by weight, especially more than 90% by weight.
• the biologically active material could be any lipo- philic, hydrophilic or amphiphilic material, as appropriate. However, preferably it is a lipophilic or amphiphilic material, especially a pharmaceutical material.
• examples of such pharmaceutical materials or compounds in connection with which the invention is especially prefe- rable are antibiotics, proteins, peptides, steroids, vitamins, nucleic acids and vaccines. Peptides, or peptide- like molecules, and proteins are of special interest as they are often of low or variable bioavailability .
• the composition also contains a fatty acid in an amount sufficient to neutralize the charge effect or to control the phase properties of the composition.
• a fatty acid in an amount sufficient to neutralize the charge effect or to control the phase properties of the composition.
• the action of said fatty acid is believed to stem from the fact that it is solubilized in the diglycerol ester phases referred to.
• the addition of said fat- ty acid can be performed as some kind of titration towards the desired phase.
• the fatty acid referred to is preferably selected from the same fatty acids as are used for the diglycerol esters present in the composition, i.e. generally from fatty acids having 6-18 carbon atoms, eg. 6-14 carbon atoms or 16-18 carbon atoms.
• the biologically active material is preferably present in the composition according to the invention in an amount of 0.1-20, more preferably 0.2-10, % by weight, based on the total weight of the composition when dissolved in the carrier.
• the biologically active material is preferably present in the composition in an amount of 0.1-40, more preferably 0.2-20, and most preferably 1-15, % by weight, based on the total weight of the composition.
• the composition according to the invention can be prepared in any conventional way, i.e. according to any of those techniques which have previously been utilized for lipid carriers, especially for monoglycerol fatty acid esters. However, further details as to the preparation can be found in the working examples presented below.
• composition of the liquid or liquid crystalline product of the invention it can be taken from a phase diagram for each and every specific combination to be used.
• amount of water (or other polar liquid) which a lamellar liquid phase contains will be in the range of 0-50%, while a cubic liquid crystalline phase will contain 20-50% thereof, a reversed hexagonal liquid crystalline phase will contain 20-40% thereof and an L2 phase will contain 0-10% thereof, all percentages being expressed as % by weight.
• the presence of small amounts of charged lipids can increase the swel- ling of the lipid structure in polar liquids in the case of the cubic and lamellar phases.
• compositions as previously defined for use as a medicament for controlled release of said biologically active material i.e. in the form of a pharmaceutical compound.
• composition is especially interesting for oral or topical delivery of the pharmaceutical compound, a very advantageous characteristic or property of the composition being that it is bioadhesive, as is for instance disclosed in connection with the working examples .
• the invention is not restricted to the incorporation of a pharmaceutically active material in the composition, still another aspect of the invention is represented by the use of the composition as previously defined for the controlled release of a biologically active non-medical material in any application where the advantages achieved by the invention could be utilized.
• the invention relates to a method of administering to a mammal, especially a human being, the composition as previously defined to the body of said mammal in an amount that is effective for the intended curative or prophylactic treatment.
• a controlled release of the biologically active material is achieved, together with other advantageous effects as stated above.
• a carrier in drug deliviery will usually be exposed to a water medium, and therefore the phase which is formed by the carrier in excess of water is significant.
• these esters form four types of aqueous phases in excess of water.
• L ⁇ lamellar liquid- crystalline phase
• a diglycerol ester of capric acid with the composition presented below was prepared by conventional esteri- fication of capric acid (98% w/w) and diglycerol (95% w/w) followed by a short-path, high-vacuum distillation, referred to as a molecular distillation
• composition was easily self-emulsifying which is a proviso for a good oral upta- ke.
• the raw materials used in this Example were commer- cial diglycerol with a purity of 92-95% of diglycerol
• the first synthesis step was an esterification reac- tion of the fatty acids with diglycerol, resulting in an equilibrium mixture of diglycerol mono-esters, diglycerol di-esters, diglycerol tri-esters and possibly traces of diglycerol tetra-esters, combined with small amount of free diglycerol and free fatty acids.
• the fatty acid composition of the diglycerol monooleate used in this example was:
• the hexagonal phase of diglycerol monoester of oleic acid, mixture of diglycerol monoester and diglycerol di- ester of oleic acid, and water 15/75/10% w/w was adhered to human skin at the upper side of the hand in an amount of approximatively 0.2-0.5 g.
• the hand was held in water with a temperature of approximatively 30°C for 15 min.
• the phase was then removed from the skin with a spatula.
• the hexagonal phase contained 10% of water and swelled in excess of water.
• the materials collected from the skin were dried to a constant weight over phosphorous pentoxi- de . The results are presented in the following table:
• Two groups of rats were gavaged using a soft stomach tube with two formulations of the nonapeptide dDAVP (106,8 ⁇ g/g), either as a saline solution or as a lipid vehicle based on diglyceride esters of capric acid.
• the composition of said lipid vehicle is shown in Table 1.
• saline was flushed (9,0 ml kg "1 body wt) through the same tubing.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Dispersion Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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Cited By (19)

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• 1997
  • 1997-01-13 SE SE9700061A patent/SE511313C2/sv not_active IP Right Cessation
• 1998
  • 1998-01-08 CA CA002277377A patent/CA2277377C/en not_active Expired - Fee Related
  • 1998-01-08 WO PCT/SE1998/000009 patent/WO1998030206A1/en not_active Ceased
  • 1998-01-08 JP JP53080298A patent/JP2001508773A/ja not_active Ceased
  • 1998-01-08 AU AU55832/98A patent/AU5583298A/en not_active Abandoned
  • 1998-01-08 AT AT98900793T patent/ATE243024T1/de not_active IP Right Cessation
  • 1998-01-08 DE DE69815659T patent/DE69815659T2/de not_active Expired - Lifetime
  • 1998-01-08 EP EP98900793A patent/EP0954287B1/en not_active Expired - Lifetime
  • 1998-01-08 US US09/341,294 patent/US6660278B1/en not_active Expired - Fee Related

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