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WO1997009978A1 - Use of esters of polyhydric alcohols to enhance the oral bioavailability of drug substances as well as novel esters and pharmaceutical compositions containing them - Google Patents

Use of esters of polyhydric alcohols to enhance the oral bioavailability of drug substances as well as novel esters and pharmaceutical compositions containing them Download PDF

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Publication number
WO1997009978A1
WO1997009978A1 PCT/DK1996/000387 DK9600387W WO9709978A1 WO 1997009978 A1 WO1997009978 A1 WO 1997009978A1 DK 9600387 W DK9600387 W DK 9600387W WO 9709978 A1 WO9709978 A1 WO 9709978A1
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Prior art keywords
carbon atoms
fatty acid
ester
esters
acid moiety
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PCT/DK1996/000387
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French (fr)
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Morten Sloth Weidner
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Morten Sloth Weidner
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Priority to AU68699/96A priority Critical patent/AU6869996A/en
Publication of WO1997009978A1 publication Critical patent/WO1997009978A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/18—Acetic acid esters of trihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom

Definitions

  • esters of polyhydric alcohols to enhance the oral bioavailability of drug substances as well as novel esters and pharmaceutical compositions containing them.
  • This invention relates to the use of certain esters of polyhydric alcohols for the preparation of pharmaceutical compositions having enhanced bioavailability of an incor ⁇ porated drug and a method for enhancing the oral bio ⁇ availability of drug substances. Further, the invention relates to a novel group of ester compounds and to phar- maceutical compositions containing them.
  • Systemically active drugs have been administered in a wide variety of ways such as orally, rectally, intrave ⁇ nously, intramuscularly, subcutanously, vaginally, in ⁇ tranasally and transdermally.
  • Today the most widely used route of administration is undoubtedly the oral one due to its convenience.
  • Orally administered drugs are generally absorbed in the intestine but typically have a poor bioavailability. The reasons for this are various:
  • Liposomes that were discovered in the 1960s. Liposomes consist of one or more concen ⁇ tric spheres of lipid bilayers surrounding aqueous com ⁇ partments. Many attempts have been made to utilise liposomes in relation to enhancing the bioavailability of drugs. This is reflected in a number of patents disclos ⁇ ing the preparation of liposomes, e.g. EP 158 441, EP 260 241 and WO 87/07502. However it has been shown that many liposomal systems are relatively unstable in the gastro- intestinal tract and that drugs incorporated into liposomes and administered orally are absorbed only to the same extent as the free drug ( Rowland and Woodley, Biochim. Biophys. Acta, 1980, 620, 400). This is probably the reason why no oral drug based on liposomes has ever been marketed.
  • fats i .e.triglycerides
  • im ⁇ prove the oral bioavailability of certain drugs. This may be due to the fact that triglycerides can shield drugs from the harsh chemical environment of the digestive sys ⁇ tem thus enhancing the stability of drugs that are unsta ⁇ ble in the stomach and intestine. Another possibility is that fats can enhance the take up of drugs via the lym ⁇ phatic system thus bypassing the liver and subsequent first pass clearance resulting in an enhanced bioavail ⁇ ability.
  • employed triglycerides are long chain triglycerides like peanut oil or medium chain triglycerides like capric/caprylic acid triglycerides.
  • compositions for oral delivery of drugs comprising non- esterified fatty acids having 14-18 carbon atoms, mono ⁇ glycerides with fatty acids having 14-18 carbon atoms, lysophosphatidylcholine in which the fatty acid component has 14-18 carbon atoms, a drug substance and optionally bicarbonate and bile salts.
  • mixed chainlength es ⁇ ters of polyhydric alcohols have an enhancing effect on the bioavailability of oral drugs, an effect which is not found when utilising traditional esters.
  • the mixed chainlength esters of polyhydric alcohols are effi ⁇ cient carriers for drugs making possible compositions with a high content of the active drug substance.
  • the present invention comprises the use of an ester of a polyhydric alcohol having 2-8 carbon atoms, said ester containing at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or unsatu ⁇ rated fatty acid moiety of 4-30 carbon atoms, for the preparation of a pharmaceutical composition comprising at least one drug substance and at least one such ester and having enhanced oral bioavailability of said drug sub ⁇ stance.
  • esters used may for example be such wherein the poly ⁇ hydric alcohol is selected from the group consisting of polyhydric hydroxyalkanes having 2-4 carbon atoms. These are:
  • polyhydric alcohols of this type are 1,2- ethanediol (ethylene glycol), 1, 2-propanediol (propylene glycol) and 1,2 , 3-propanetriol (glycerol).
  • esters used may also be such wherein the polyhydric alcohol is selected from the group consisting of monosac ⁇ charides, preferably pentoses and hexoses, and their cor ⁇ responding sugar alcohols and desoxy sugars.
  • Preferred polyhydric alcohols of this type are glucose and sorbi- toi.
  • the or each short-chain fatty acid moiety of 1-3 carbon atoms is preferably acetyl; and the or each long-chain fatty acid moiety of 4-30 carbon atoms is preferably a moiety of 8- 22 carbon atoms such as octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, linoloyl and li- nolenoyl .
  • esters for use according to the inven ⁇ tion are acetylated glycerol or sorbitan monoesters hav ⁇ ing a fatty acid moiety of 4-30 carbon atoms, and pref ⁇ erably 8-22 carbon atoms.
  • the pharmaceutical composition prepared by the use ac ⁇ cording to the invention preferably comprises two or more of the mentioned esters.
  • the esters used according to the inven- tion are termed mixed-chainlength-esters .
  • the ratio be ⁇ tween the mixed-chainlength-esters and the drug of the composition would normally be in the range of 1-90 % drug to 10-99 % mixed-chainlength-esters by weight.
  • an even higher proportion of mixed-chainlength-esters may be used.
  • the mixed-chainlength-esters used according to the invention can be formulated with a broad spectrum of drugs for en ⁇ hanced oral bioavailability.
  • composition prepared by the use accord ⁇ ing to the invention may contain additives such as sur ⁇ factants, solvents, thickeners, stabilisers, preserva ⁇ tives, antioxidants, flavourings etc. to obtain a desir- able product formulation.
  • additives such as sur ⁇ factants, solvents, thickeners, stabilisers, preserva ⁇ tives, antioxidants, flavourings etc.
  • dosage form of the formulation tablets, gelatine cap ⁇ sules, fluids or granulates are envisaged.
  • composition may contain surfactants such as bile salts or polyoxyethylene-sorbitan-fatty acid es ⁇ ters for improving dispersibility of the composition in the digestive fluids or for obtaining the final dosage form of the composition.
  • surfactants such as bile salts or polyoxyethylene-sorbitan-fatty acid es ⁇ ters for improving dispersibility of the composition in the digestive fluids or for obtaining the final dosage form of the composition.
  • the present invention also provides a method of enhancing the oral bioavailability of drug substances which com ⁇ prises admixing with a drug substance or drug formulation at least one ester of a polyhydric alcohol having 2-8 carbon atoms, said ester containing at least one fatty acid moiety of 1-3 carbon atoms and at least one satu ⁇ rated or unsaturated fatty acid moiety of 4-30 carbon at ⁇ oms .
  • esters preferred in the carrying out of this method are the same as those preferred in the use for the prepa ⁇ ration of a pharmaceutical composition as described above.
  • the mixed chainlength esters used according to the present invention are novel compounds, and therefor the inven ⁇ tion also comprises an ester of a polyhydric alcohol ha ⁇ ving 2-8 carbon atoms, except glycerol, said ester con ⁇ taining at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or unsaturated fatty a- cid moiety of 4-30 carbon atoms.
  • the invention comprises a pharmaceutical prepa- ration comprising at least one drug substance and at le ⁇ ast one of the novel esters described above.
  • composition of the invention is fully dispersible in the fluids of the digestive system and forms mi ⁇ Solutions under influence of bile salts in the intestine making the drug more available for absorption.
  • the mixed-chainlength-esters provide a stable environment in which precipitation of the drug is avoided. This is accomplished even though the composition may consist of up to 75% of the pure drug substance.
  • the mixed-chainlength-esters of the invention represent an environment in which the drug is compatible with or soluble in fats.
  • the drug of the composition may to a greater extent be co-absorbed with fats into the lymphatic system thus avoiding first pass clearance. Fats are absorbed in a region of the intestine where metabolism is limited.
  • the fat absorbed by the villi of the intestinal mucosa is transported into a lymphatic vessel and further through the tho- racic duct, the major lymphatic channel and is conse ⁇ quently emptied into the blood circulation. In this way it is not carried in the portal blood leading directly to the liver where first pass metabolism occurs.
  • composition prepared by the use according to the in ⁇ vention comprises the following:
  • drug as used herein and in the accompanying claims is broadly de- fined as any chemical agent or chemical substance which affects living processes. For example this could be substances administered for therapeutic, prophylac ⁇ tic, diagnostic or general health-promoting purposes, including pure substances and vitamins, combinations of substances and complex mixtures of substances such as plant extracts or fractions thereof.
  • drug as used herein and in the accompanying claims is broadly de- fined as any chemical agent or chemical substance which affects living processes. For example this could be substances administered for therapeutic, prophylac ⁇ tic, diagnostic or general health-promoting purposes, including pure substances and vitamins, combinations of substances and complex mixtures of substances such as plant extracts or fractions thereof.
  • the mixed- chainlength-esters according to the invention can be formulated with a broad spectrum of drugs for enhanced oral bioavailability.
  • Cholinoceptor-activating and cholinesterase-inhibiting drugs like acethylcholine, bethanechol, carbachol, pi- locarpine, ambenonium, demecarium, echothiophate, edrophonium, isoflurophate, neostigmine, physostig ⁇ mine, eserine, etc.; cholinoceptor-blocking drugs like anisotropine, atropine, belladonna alkaloids, clidi- niu , cyclopentolate, dicyclomine, flavoxate, gly- copyrrolate, hexocyclium, ho atropine, isopropamide, 1-hyoscyamine, ipratropium, mepenzolate, ethanthe- line, methscopolamine, oxybutynin, oxyphencyclimine, pr ⁇ pantheline, scopolamine, tridihexethyl, tropi- camide
  • adrenoceptor-activating and other sympathomimetic drugs like amphetamine, apraclonidine, dextroa pheta- mine, dobutamine, dopamine, ephedrine, epinephrine, isoproterenol, mephentermine, metaraminol, metha - phetamine, methoxamine, methylphenidate, naphazoline, norepinephrine, oxymetazoline, phenmetrazine, phen ⁇ ylephrine, phenylpropanolamine, pseudoephedrine, tet- rahydrozoline, xylometazoline etc.; adrenoceptor- blocking drugs like doxazosin, phenoxybenzamine, phen- tolamine, prazosin, terazosin, tolazoline, acebutolol , atenolol, betaxolol,
  • alcohol intake prevention like disulfiram; antiepi ⁇ leptic drugs like carbamazepine, clorazepate dipotas ⁇ sium, ethosuximide, ethotoin, gabapentin, mephenytoin, methsuximide, paramethadione, phenace ide, pensuxi- mede, phenytoin, primidone, trimethadione, valproic acid etc.; spasmolytics like baclofen, cyclobenza- prine, dantrolene etc.; drugs for movement disorders like amantadin, benztropine, biperiden, bromocriptine, carbidopa, levodopa, orphenadrine, penicillamine, per- golide, procyclidine, selegiline(deprenyl) , trientine, trihexyphenidyl etc.; antipsychotic drugs like aceto- phenazine, chlorpromazine,
  • compositions by the use according to the invention with substances ranging from a heavy and very lipophilic substance like coenzyme QIO to a more hydrophilic substance like aspirin.
  • the preferred drug for the use according to the invention is a relatively lipophilic substance.
  • the alcohol of the ester may for example be selected among polyhydric hydroxyalkanes having 2-4 carbon at ⁇ oms, i.e. 1, 2-ethanediol (ethylene glycol)
  • the alcohol of the ester may for example also be se ⁇ lected among monosaccharides and their corresponding sugar alcohols and desoxy sugars, preferably among pentoses and hexoses and their corresponding sugar al ⁇ cohols and desoxy sugars.
  • esters of monosaccharides and sugar alco ⁇ hols are acetylated fatty acid esters of sorbitol ( e *9* acetylated sorbitan monooleate) or acetylated fatty acid esters of glucose.
  • esters of polyhydric hydroxyalkanes are esters of 1, 2-ethanediol (ethylene glycol), 1,2- propanediol (propylene glycol) or 1,2, 3-propanetriol (glycerol) which are preferred due to their well known low toxicity.
  • esters having an acetic acid moiety (2:0) as the short chain are also espe ⁇ cially preferred. As illustrated in the experimental section these esters are expected to have a broad range of applications.
  • esters of 1,2, 3-propanetriol having one or two acetic acid (2:0) moieties as short chains and one of the following fatty acids as the long chain: caprylic acid (8:0), capric acid (10:0), lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), linolic acid (18:2) or linolenic acid (18:3).
  • composition may contain additives such as surfactants, solvents, thickeners, stabilisers, preservatives, antioxidants, flavour etc. to obtain a desirable product formulation.
  • additives such as surfactants, solvents, thickeners, stabilisers, preservatives, antioxidants, flavour etc.
  • the ratio between the mixed-chainlength-esters and the drug of the composition would typically be 1-75 % drug and 25-99 % mixed-chainlength-esters by weight.
  • the pharmaceutical composition can be prepared by the use of the invention in several ways depending on the drug.
  • the mixed-chainlength-esters provide the convenience that they can be prepared especially to suit different drugs so that a high solubility of the drug in the mixed- chainlength-esters can be accomplished resulting in a high possible dosage of the drug.
  • the drug and the mixed-chainlength-esters can be mixed without employing an organic solvent. How- ever, in many cases the basic mixture of the drug and the mixed-chainlength-ester is more easily prepared by dis ⁇ solving the drug in an appropriate organic solvent, mix ⁇ ing it with the mixed-chainlength-ester(s) and subse ⁇ quently removing the solvent by evaporation.
  • incorpo ⁇ rate surfactants or stabilisers it is advantageous or necessary to incorpo ⁇ rate surfactants or stabilisers to obtain a workable and stable composition.
  • qualities of the composition may be varied by varying the mixed-chainlength-esters.
  • employed additives may influence certain characteristics of the composition. For instance the rate of release and dispersion of the formulation in the digestive system can be increased by incorporating appropriate surfactants, such as bile salts, polyoxyeth ⁇ ylene glycolated vegetable oils (e.g. Cre aphor) or polyoxyethylene-sorbitan-fatty acid esters (e.g. Polysor ⁇ bate) .
  • numer ⁇ ous different additives for example solvents, preserva- tives, antioxidants, thickeners, colourings , etc. may be employed to obtain a suitable product for oral admini ⁇ stration.
  • the composition can be administered orally in any form, for example in tablets, capsules, powders or as a liquid.
  • Example 1 Providesterone mixed-chainlength-esters composi ⁇ tion.
  • progesterone (some of which was tagged with H) was added to 20,00 g of a mixture of mixed-chainlength- esters of 1,2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composi ⁇ tion in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • the radioactivity of both preparations was 27 ⁇ Ci/g.
  • Example 2 Retinol mixed-chainlength-esters composition
  • retinol (some of which was tagged with H) was added to 4,750 g of a mixture of mixed-chainlength-esters of 1,2 , 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 10 % palmitic (16:0), 10 % stearic acid (18:0), 70 % oleic acid (18:l)and 10 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety ⁇ lated and 10 % were monoacetylated.
  • the composition was gently stirred at 60 °C.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • the radioactivity of both preparations was 27 ⁇ Ci/g.
  • MCE mixed-chainlength- esters
  • the bioavailability of the mixed-chainlength-esters for ⁇ mulation was 33,9 % better than the peanut oil formula ⁇ tion measured as the AUC.
  • Example 3 (Acyclovir mixed-chainlength-esters composi ⁇ tion) .
  • acyclovir was added to 20,00 g of a mixture of mixed-chainlength-esters of 1,2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety- lated and 10 % were monoacetylated.
  • Example 4 ( ⁇ -tocopherol mixed-chainlength-esters composi ⁇ tion) .
  • dl- ⁇ -tocopherol was added to 10,00 g of a mix ⁇ ture of mixed-chainlength-esters of 1, 2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 10 % palmitic (16:0), 10 % stearic acid (18:0), 70 % oleic acid (18:1) and 10 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
  • the composition was gently stirred at 60 °C.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • Example 5 (Ibuprofen mixed-chainlength-esters composi ⁇ tion) .
  • ibuprofen was added to 5,00 g of a mixture of mixed-chainlength-esters of 1,2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety ⁇ lated and 10 % were monoacetylated.
  • the composition was gently stirred at 60 °C.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • composition was stored for 12 weeks at 0-5 °C and no precipitation of ibuprofen occurred.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • Example 7 (Coenzyme Q10 mixed-chainlength-esters composi ⁇ tion) .
  • 2,00 g of coenzyme QIO was added to 8,00 g of a mixture of mixed-chainlength-esters of 1, 2, 3-propanetriol (glyce ⁇ rol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety ⁇ lated and 10 % were monoace
  • the composition was gently stirred at 60 C.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • composition was filled in hard gelatine capsules (0,5 ml) and stored for 12 months at room temperature (20-25 C).
  • the composition was found to be stable and no pre ⁇ cipitation of coenzyme Q10 was observed as evaluated by microscopy (400-900 x magnification with phase contrast).
  • MCE mixed-chainlength- esters
  • the bioavailability of the mixed-chainlength-esters for ⁇ mulation was 71,4 % better than that of the soybean oil formulation measured as the AUC.
  • Example 8 (Ginkgo biloba mixed-chainlength-esters compo ⁇ sition) .
  • Ginkgo biloba extract dry residue of alcoholic extract
  • glycerol 1,2,3-propanetriol
  • acetic acid 2:0
  • one of the fol ⁇ lowing fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % ca ⁇ pric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approxi ⁇ mately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
  • the composition was gently stirred at 60 °C. Ethanol was used as a solvent and was subsequently removed by evapo ⁇ ration.
  • Example 9 (Ginger mixed-chainlength-esters composition).
  • 10,00 g of Ginger extract dry residue of alcoholic ex ⁇ tract was added to 10,00 g of a mixture of mixed- chainlength-esters of 1, 2 , 3-pro ⁇ anetriol (glycerol) with acetic acid (2:0) as the short chain and one of the fol ⁇ lowing fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % ca ⁇ pric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0) 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approxi ⁇ mately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
  • the composition was gently stirred at 60 °C .
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • MCE mixed-chainlength- esters
  • the bioavailability of the mixed-chainlength-esters for ⁇ mulation was 120,9 % better than that of the soybean oil formulation measured as the AUC.
  • Example 10 (Echinacea mixed-chainlength-esters composi ⁇ tion) .
  • Echinacea extract dry residue of hydroalco ⁇ holic extract
  • acetic acid (2:0) as the short chain
  • one of the fol ⁇ lowing fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % ca ⁇ pric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain.
  • the mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approxi ⁇ mately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
  • Example 11 (Coenzyme Q10 mixed-chainlength-esters compo ⁇ sition) .
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo- geneous and stable at room temperature.
  • Example 12 (Garlic mixed-chainlength-esters composition).
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • Parthenium integrifolium extract dry residue of alcoholic extract
  • acetylated sor- bitan monooleate 3,0 g of acetylated sor- bitan monooleate.
  • the mixed-chainlength-ester was pre ⁇ pared by reacting sorbitan monooleate with acetic anhy ⁇ dride.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.
  • composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo ⁇ geneous and stable at room temperature.

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Abstract

Esters of polyhydric alcohols having 2-8 carbon atoms, said esters containing at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or unsaturated fatty acid moiety of 4-30 carbon atoms, are used for the preparation of pharmaceutical compositions comprising at least one drug substance and at least one such ester and having enhanced oral bioavailability of the drug substance. A method of enhancing the oral bioavailability of drug substances comprises admixing at least one such ester with a drug substance or drug formulation. The esters, except those of glycerol, are novel compounds.

Description

Use of esters of polyhydric alcohols to enhance the oral bioavailability of drug substances as well as novel esters and pharmaceutical compositions containing them.
FIELD OF THE INVENTION
This invention relates to the use of certain esters of polyhydric alcohols for the preparation of pharmaceutical compositions having enhanced bioavailability of an incor¬ porated drug and a method for enhancing the oral bio¬ availability of drug substances. Further, the invention relates to a novel group of ester compounds and to phar- maceutical compositions containing them.
BACKGROUND OF THE INVENTION
Systemically active drugs have been administered in a wide variety of ways such as orally, rectally, intrave¬ nously, intramuscularly, subcutanously, vaginally, in¬ tranasally and transdermally. Today the most widely used route of administration is undoubtedly the oral one due to its convenience.
Orally administered drugs are generally absorbed in the intestine but typically have a poor bioavailability. The reasons for this are various:
• Many drugs are poorly dissolved in the chemical envi¬ ronment of the gastric or intestinal fluids.
• Many drugs are adversely affected by the pH and the en¬ zymatic activity of the stomach and the intestine.
• Many drugs undergo first pass clearance, i.e. they are converted in the intestine or the liver into phar a- cologically inactive metabolites and/or are secreted into the bile by the liver either as they are or as ac¬ tive metabolites.
• Many drugs are poorly absorbed through the intestinal mucosa.
The consequence of this is that in many cases only a mi¬ nor part of an orally administered dose of a drug reaches systemic circulation.
Numerous attempts have been made to improve the bioavail¬ ability of orally administered drugs.
An example of this are the liposomes that were discovered in the 1960s. Liposomes consist of one or more concen¬ tric spheres of lipid bilayers surrounding aqueous com¬ partments. Many attempts have been made to utilise liposomes in relation to enhancing the bioavailability of drugs. This is reflected in a number of patents disclos¬ ing the preparation of liposomes, e.g. EP 158 441, EP 260 241 and WO 87/07502. However it has been shown that many liposomal systems are relatively unstable in the gastro- intestinal tract and that drugs incorporated into liposomes and administered orally are absorbed only to the same extent as the free drug ( Rowland and Woodley, Biochim. Biophys. Acta, 1980, 620, 400). This is probably the reason why no oral drug based on liposomes has ever been marketed.
A more promising attempt is the biosome disclosed in WO 92/05771. Here the drug formulation is a precursor to liposome-like structures that are formed in vivo. However there is to our knowledge no evidence of biosomes enhanc- ing the bioavailability of oral drugs.
It is generally known that fats, i .e.triglycerides, im¬ prove the oral bioavailability of certain drugs. This may be due to the fact that triglycerides can shield drugs from the harsh chemical environment of the digestive sys¬ tem thus enhancing the stability of drugs that are unsta¬ ble in the stomach and intestine. Another possibility is that fats can enhance the take up of drugs via the lym¬ phatic system thus bypassing the liver and subsequent first pass clearance resulting in an enhanced bioavail¬ ability. Traditionally employed triglycerides are long chain triglycerides like peanut oil or medium chain triglycerides like capric/caprylic acid triglycerides.
It has been shown that a higher effect of the hormone testosterone undecanoate can be achieved if the drug is administered in peanut oil solution as compared to ad¬ ministration in an aqueous microcrystalline suspension ( Coert et al . , Acta Endocrinol . , 1975, 79, 789) ( Hirschhauser et al . , Acta Endocrinol., 1975, 80, 179). This is considered to be due to enhanced take up of the drug via the thoracic lymph thus avoiding first pass clearance by the liver.
It is generally known that surfactants such as bile salts or polyoxyethylene-sorbitan-fatty acid esters can enhance absorption of drugs. Thus, the utilisation of fats and oils for oral drug delivery has also often been in the form of emulsions where surfactants are also employed. Several examples are reported in the literature where this strategy has resulted in an enhanced absorption of drugs:
• griseofulvin in an oil-in-water emulsion ( Bates et al . , J. Pharm. Sci., 1975, 64, 793) .
• cefoxitin in an oil-in-water emulsion ( Pal in et al . , Int. J. Pharm., 1986, 33, 99).
• cyclosporine in microemulsion (Tarr et al . , Pharm. Res. , 1989, 6, 40) .
In WO 86/05694 and WO 92/03121 by Yesair compositions for oral delivery of drugs are disclosed comprising non- esterified fatty acids having 14-18 carbon atoms, mono¬ glycerides with fatty acids having 14-18 carbon atoms, lysophosphatidylcholine in which the fatty acid component has 14-18 carbon atoms, a drug substance and optionally bicarbonate and bile salts.
SUMMARY OF THE INVENTION
Surprisingly it has been found that mixed chainlength es¬ ters of polyhydric alcohols have an enhancing effect on the bioavailability of oral drugs, an effect which is not found when utilising traditional esters. In addition the mixed chainlength esters of polyhydric alcohols are effi¬ cient carriers for drugs making possible compositions with a high content of the active drug substance.
Accordingly the present invention comprises the use of an ester of a polyhydric alcohol having 2-8 carbon atoms, said ester containing at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or unsatu¬ rated fatty acid moiety of 4-30 carbon atoms, for the preparation of a pharmaceutical composition comprising at least one drug substance and at least one such ester and having enhanced oral bioavailability of said drug sub¬ stance..
The esters used may for example be such wherein the poly¬ hydric alcohol is selected from the group consisting of polyhydric hydroxyalkanes having 2-4 carbon atoms. These are:
1, 2-ethanediol (ethylene glycol) 1, 2-propanediol (propylene glycol) 1 , 3-propanediol 1, 2 , 3-propanetriol (glycerol) 1 , 2-butanediol 1, 3-butanediol 1 , 4-butanediol
1,2, 3-butanetriol
1 , 2 ,4-butanetriol and
1,2,3, 4-butanetetraol . Preferred polyhydric alcohols of this type are 1,2- ethanediol (ethylene glycol), 1, 2-propanediol (propylene glycol) and 1,2 , 3-propanetriol (glycerol).
The esters used may also be such wherein the polyhydric alcohol is selected from the group consisting of monosac¬ charides, preferably pentoses and hexoses, and their cor¬ responding sugar alcohols and desoxy sugars. Preferred polyhydric alcohols of this type are glucose and sorbi- toi.
In the esters used according to the invention the or each short-chain fatty acid moiety of 1-3 carbon atoms is preferably acetyl; and the or each long-chain fatty acid moiety of 4-30 carbon atoms is preferably a moiety of 8- 22 carbon atoms such as octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, linoloyl and li- nolenoyl .
The most preferred esters for use according to the inven¬ tion are acetylated glycerol or sorbitan monoesters hav¬ ing a fatty acid moiety of 4-30 carbon atoms, and pref¬ erably 8-22 carbon atoms.
The pharmaceutical composition prepared by the use ac¬ cording to the invention preferably comprises two or more of the mentioned esters.
In the following the esters used according to the inven- tion are termed mixed-chainlength-esters . The ratio be¬ tween the mixed-chainlength-esters and the drug of the composition would normally be in the range of 1-90 % drug to 10-99 % mixed-chainlength-esters by weight. In the case of drugs having a very high biological activity and thus to be administered in very low unit dosages an even higher proportion of mixed-chainlength-esters may be used. On the basis of experiments it is expected that the mixed-chainlength-esters used according to the invention can be formulated with a broad spectrum of drugs for en¬ hanced oral bioavailability.
Additionally the composition prepared by the use accord¬ ing to the invention may contain additives such as sur¬ factants, solvents, thickeners, stabilisers, preserva¬ tives, antioxidants, flavourings etc. to obtain a desir- able product formulation. There are no limitations to the dosage form of the formulation but tablets, gelatine cap¬ sules, fluids or granulates are envisaged.
Optionally the composition may contain surfactants such as bile salts or polyoxyethylene-sorbitan-fatty acid es¬ ters for improving dispersibility of the composition in the digestive fluids or for obtaining the final dosage form of the composition.
The present invention also provides a method of enhancing the oral bioavailability of drug substances which com¬ prises admixing with a drug substance or drug formulation at least one ester of a polyhydric alcohol having 2-8 carbon atoms, said ester containing at least one fatty acid moiety of 1-3 carbon atoms and at least one satu¬ rated or unsaturated fatty acid moiety of 4-30 carbon at¬ oms .
The esters preferred in the carrying out of this method are the same as those preferred in the use for the prepa¬ ration of a pharmaceutical composition as described above.
To the best of our knowledge the mixed chainlength esters used according to the present invention, except the glyc¬ erol esters, are novel compounds, and therefor the inven¬ tion also comprises an ester of a polyhydric alcohol ha¬ ving 2-8 carbon atoms, except glycerol, said ester con¬ taining at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or unsaturated fatty a- cid moiety of 4-30 carbon atoms.
Further, the invention comprises a pharmaceutical prepa- ration comprising at least one drug substance and at le¬ ast one of the novel esters described above.
DETAILED DESCRIPTION OF THE INVENTION
The preparation of a pharmaceutical composition by the use according to the invention provides a unique solution to some of the basic problems of bioavailability:
• Many drugs have a low bioavailability due to the fact that they are poorly dissolved in the gastric and in- testinal fluids and therefore are not available for ab¬ sorption in the intestine after oral administration. The composition of the invention is fully dispersible in the fluids of the digestive system and forms mi¬ celles under influence of bile salts in the intestine making the drug more available for absorption. The mixed-chainlength-esters provide a stable environment in which precipitation of the drug is avoided. This is accomplished even though the composition may consist of up to 75% of the pure drug substance.
• Many drugs are adversely affected by the pH and the en¬ zymatic activity of the stomach and the intestine which contributes to a poor bioavailability. In the composi¬ tion of the invention the drug substance is shielded against the harsh chemical environment of the digestive system and thus protected against degradation.
• Many drugs have a poor bioavailability because they un¬ dergo first pass clearance, i.e. they are converted in the intestine or the liver into pharmacologically inac¬ tive metabolites and/or are secreted into the bile by the liver either as they are or as active metabolites. The mixed-chainlength-esters of the invention represent an environment in which the drug is compatible with or soluble in fats. Thus it is possible that the drug of the composition may to a greater extent be co-absorbed with fats into the lymphatic system thus avoiding first pass clearance. Fats are absorbed in a region of the intestine where metabolism is limited. The fat absorbed by the villi of the intestinal mucosa is transported into a lymphatic vessel and further through the tho- racic duct, the major lymphatic channel and is conse¬ quently emptied into the blood circulation. In this way it is not carried in the portal blood leading directly to the liver where first pass metabolism occurs.
• Many drugs have a low bioavailability simply because they are not absorbed well through the intestinal mu¬ cosa. Surprisingly it has been found that the mixed- chainlength-esters of the invention can enhance the ab¬ sorption of drug substances. Many strategies have pre- viously been proposed for the improvement of drug ab¬ sorption based on the use of surfactants as drug ab¬ sorption enhancers . The drawback of many surfactants is that they cause adverse reactions in the doses neces¬ sary for an absorption enhancement and that they often do not provide a stable environment for the drug. The esters of the invention are non-toxic and well toler¬ ated even in high doses and provide a stable environ¬ ment for the drug substance.
The composition prepared by the use according to the in¬ vention comprises the following:
1. At least one drug substance. The term "drug" as used herein and in the accompanying claims is broadly de- fined as any chemical agent or chemical substance which affects living processes. For example this could be substances administered for therapeutic, prophylac¬ tic, diagnostic or general health-promoting purposes, including pure substances and vitamins, combinations of substances and complex mixtures of substances such as plant extracts or fractions thereof. On the basis of experiments it is expected that the mixed- chainlength-esters according to the invention can be formulated with a broad spectrum of drugs for enhanced oral bioavailability. The following are non-limiting examples of such drugs:
Cholinoceptor-activating and cholinesterase-inhibiting drugs like acethylcholine, bethanechol, carbachol, pi- locarpine, ambenonium, demecarium, echothiophate, edrophonium, isoflurophate, neostigmine, physostig¬ mine, eserine, etc.; cholinoceptor-blocking drugs like anisotropine, atropine, belladonna alkaloids, clidi- niu , cyclopentolate, dicyclomine, flavoxate, gly- copyrrolate, hexocyclium, ho atropine, isopropamide, 1-hyoscyamine, ipratropium, mepenzolate, ethanthe- line, methscopolamine, oxybutynin, oxyphencyclimine, prσpantheline, scopolamine, tridihexethyl, tropi- camide, mecamylamine, trimethaphan camsylate etc.; cholinesterase regenerators such as pralidoxime etc. ; adrenoceptor-activating and other sympathomimetic drugs like amphetamine, apraclonidine, dextroa pheta- mine, dobutamine, dopamine, ephedrine, epinephrine, isoproterenol, mephentermine, metaraminol, metha - phetamine, methoxamine, methylphenidate, naphazoline, norepinephrine, oxymetazoline, phenmetrazine, phen¬ ylephrine, phenylpropanolamine, pseudoephedrine, tet- rahydrozoline, xylometazoline etc.; adrenoceptor- blocking drugs like doxazosin, phenoxybenzamine, phen- tolamine, prazosin, terazosin, tolazoline, acebutolol , atenolol, betaxolol, bisoprolol, carteolol, esmolol, labetolol, levobunolol, metipranolol, metoprolol, nadolol, penbutolol, pindolol, propranolol, sotalol, timolol, metyrosine etc.; antihypertensive drugs like clonidine, guanabenz, guanfacine, methyldopa, guanad- rel, guanethidine, reserpine, mecamylamine, tri¬ methaphan, diazoxide, hydralazine, minoxidil , nitro- prussid, amlodipine, diltiazem, felodipine, isradip- ine, nicardipine, nifedipine, verapamil, benazepril, captopril, enalapril, fosinopril, lisinopril, quin- april, perindopril, ramipril etc.; vasodilators like amyl nitrite, erythrityl tetranitrate, isosorbid dini- trate, isosorbid mononitrate, nitroglycerin, pen¬ taerythritol teranitrate, bepridil, ni odipine etc.; drugs used in congestive heart failure like desla- noside, digitoxin, digoxin, amrinone, milrinone etc.; drugs used in cardiac arrhythmias like amiodarone, disopyramid, flecainide, lidocaine, exiletine, mori- cizine, procainamide, propafenone, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, to- cainide, bretyliu etc.; diuretic agents like acetaxo- lamid, a iloride, bendroflu ethiazide, benzthiazide, bumetanide, chlorothiazide, demeclocycline, dichlor- phena ide, ethacrynic acid, furosemid, hydrochlorothi- azide, hydroflumethiazide, indapamide, methyclothia- zide, metolazone, polythiazide, quinethazone, spiro- nolactone, torse ide, triamterene, trichlormethiazide etc.; antihistamines like astemizole, azatadine, brom- pheniramine, buclizine, carbinoxa ine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyprohep- tadine, dexchlorpheniramine, dimenhydrinate, dihpenhy- dramine, hydroxyzine, loratidine, eclizine, methdi- lazine, phenindamine, promethazine, pyrilamine, terfe- nadine, trimeprazine, tripelennamine, triprolidine etc.; H2-receptorblockers like cimetidine, famotidine, nizatidine, ranitidine etc.; 5-HT antagonists like on- dasetron etc.; ergot alkaloids like ergonovine, ergo- tamine, ergotamine tartrate, methylergonovine, methy- sergide etc.; eicosanoids like misoprostol etc.; drugs used in asthma like albuterol, metaproterenol , terbu- taline, cromolyne sodium, aminophylline, oxtriphyl- line, theophylline, dyphylline, pentoxifylline etc.; sedative-hypnotic drugs like alprazolam, chlordi- azepoxide, clorazepate, clonazepa , diazepam, estazo- lam, flurazepa , halazepam, lorazepam, midazolam, ox¬ azepam, prazepam, quazepam, temazepam, triazolam, amo- barbital, aprobarbital , butabarbital , ephobarbital, metharbital, pentobarbital, phenobarbital, secobarbi- tal, talbutal, buspirone, chloral hydrate, eth- chlorvynol, ethinamate, glutethimide, hydroxyzine, meproba ate, methyprylon, paraldehyde, zolpidem etc . ; alcohol intake prevention like disulfiram; antiepi¬ leptic drugs like carbamazepine, clorazepate dipotas¬ sium, ethosuximide, ethotoin, gabapentin, mephenytoin, methsuximide, paramethadione, phenace ide, pensuxi- mede, phenytoin, primidone, trimethadione, valproic acid etc.; spasmolytics like baclofen, cyclobenza- prine, dantrolene etc.; drugs for movement disorders like amantadin, benztropine, biperiden, bromocriptine, carbidopa, levodopa, orphenadrine, penicillamine, per- golide, procyclidine, selegiline(deprenyl) , trientine, trihexyphenidyl etc.; antipsychotic drugs like aceto- phenazine, chlorpromazine, chlorprothixene, clozapine, fluphenaxine, fluphenzine, haloperidol, loxapine, mesoridazine, molindone, perphenazine, pimozide, pro- chlorperazine, promazine, risperidone, thioridazine, thiothixene, trifluoperazine, triflupromazine etc.; antidepressant drugs like amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, pro- triptyline, trimipramine, amoxapine, bupropion, mapro- tiline, trazodone, venlafaxine, fluoxetine, paroxet- ine, setraline, isocarboxazid, phenelzine, tranyl- cypromine etc.; opioid analgesics like codeine sul¬ fate, codeine phosphate, hydromorphone, levomethadyl acetat, tramadol hydrochloride, levorphanol, meperi- dine, methadone, morphine sulphate, oxycodone, penta- zocine, propoxyphene etc.; nonopioid analgesics like acetaminophen; nonsteroidal anti-inflammatory drugs like acetylsalicylic acid, choline salicylate, diflu- nisal, magnesium salicylate, salsalate, sodium salicy¬ late, diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, me- clofenamate sodium, mefenamic acid, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, au- ranofin, hydroxychloroquine, methotrexate, sulfasala- zine etc.; drugs used in gout like allopurinol, chol- chicine, probenecid, sulfinpyrazone etc.; antitussives like dextromethorphan etc.; drugs used in anemias like folic acid, vitamin B12 etc.; drugs used in disorders of coagulation like aminocaproic acid, dipyridamole, phytonadione, ticlopidine, tranexamic acid, warfarin etc.; drugs used in hyperlipidemia like clofibrate, fenofibrate, fluvastatin, gemfibrozil, lovastatin, neomycin, niacin, nicotinic acid, pravastatin, probu- col, simvastatin etc.; thyroid agents like levothyrox- ine, liothyronine, liotrix etc.; antithyroid agents like methimazole propylthiouracil, iopanoid acid etc.; adrenocorticosteroids like betamathasone, cortisone, dexamethasone, hydrocortisone (cortisol), hydrocorti¬ sone cypionate, methylprednisolone, prednisolone, prednisone, triamcinolone etc.; mineralocorticoids like fludrocortisone acetate etc.; adrenal steroid in¬ hibitors like amnioglutethimide, ketoconazole, me- tyrapone, mitotane, trilostane etc.; gonodal hormones like chlorotranisene, conjugated estrogens, diethyl- stilbestrol, estradiol, estropipate, ethinyl estra¬ diol, quinestrol, medroxyprogesterone acetate, mege- strol, norethindrone, norethindrone acetate, norge- strel, fluoxymesterone, methyltestosterone, oxandro- lone, oxymetholone, stanozolol, testolactone etc.; an- tagonists and inhibitors of gonodal hormones like clo- miphene, danazol, finasteride, flutamide, tamoxifen etc.; antidiabetic drugs like acetohexa ide, chlor- propamide, glipizide, glyburide, tolazamide, tolbu- tamide etc.; drugs that affect bone mineral homeosta- sis like calcifediol, calcitriol, cholecalciferol, di- hydrotachysterol, ergocalciferol, etidronate, pamidro- nate, plicamycin etc., antibiotics like tetracyclines, polymyxins, aminoglycosides, capreomycin, cycloserine, ethambutol, ethiona ide, isoniazid, pyrazinamide, ri- fabutin, rifampin, streptomycin, dapsone, clofazimine, trimetopri , sulfonamides, bacitracin, cinoxacin, ciprofloxacin, clindamycin, enoxacin, erythromycin, lincomycin, lomefloxacin, methenamine, metronidazol, methenamine mandelate, nalidixic acid, nitrofurantoin, norfloxacin, novobiocin, ofloxacin, vancomycin etc.; antifungal drugs like amphotericin B, fluconazol, flucytosine, itraconazole, ketoconazole, miconazole, griseofulvin etc.; antiviral drugs and profylaxis like acyclovir, amantadine, didanosine, rimantadine, zal- citabine, zidovudine etc.; antiprotozoal drugs like chloroquine phosphate, dehydroemetine, diloxanide fu- roate, doxycycline, iodoquinol, mefloquine, paromycin, primaquine, proguanil, pyrimetha ine, quinacrine, qui- nine sulfate, stibogluconate, sulfamethoxazol etc.; antielmintic drugs like albendazole, bithionol, dieth- ylcarbamazine, ivermectin, levamisole, mebendazole, metrifonate, niclosamide, oxamniquine, ozantel pamo- ate, piperazine, praziquantel , pyrantel pamoate, thia- bendazole etc., cancer chemotherapeutic drugs like al¬ kylating agents, procarbazine, dacarbazine, atreta- mine, cisplatin, antimetabolites, purin antagonists, pyrimidin antagonists like fluorouracil etc., plant alkaloids like vinblastine, vincristine, podophyllo- toxins, paclitaxel etc., anthracyclines, amsacrine, asparginase, hydroxyurea, mitotane, mitoxantrone, qui¬ nacrine, retinoic acid derivatives; immuno modulating drugs like axathioprine, cyclophosphamide, cyclospor¬ ine, interferon beta-lb, tacrolimus etc.; vitamins like tocopherols, retinoids, calciferols, phylloqui- nones, menaquinones etc.; natural/herbal drugs like Agrimony, Aloe, Angelica, Aniseed, Artichoke, Arnica, Balm, Bearberry, Belladonna, Bilberry, Birch, Bitter¬ sweet, Boldo, Buchu, Burdock, Butchers Broom, Cal a- mus, Capsicum, Caraway, Cascara sagrada, Celandine, Celery, Centaury, Chaste Tree, Cinchona, Clivers, Co- hosh, Common Ivy, Coneflower, Couch Grass, Cowslip, Cramp Bark, Curcuma, Dandelion, Devil s Claw, Dog Ro¬ se, Echinacea, Elder, False Hellebore, Fennel, Frangu- la, Fucus , Fumitory, Garlic, Gentian, Ginger, Ginkgo biloba, Ginseng, Golden Rod, Golden Seal, Gotu Kola, Grape Vine, Grindelia, Ground Ivy, Guaiacum, Guarana, Hawthorn, Hawthorn berries, Hops, Horehound (Black and White), Horse Chestnut, Horsetail, Hyoscyamus, Iceland Moss, Ipecacuanha, Janbul, Java Tea, Kava Kava, Kelp, Kidney Bean, Knotweed, Kola Nut, Kra eria, Lavender, Lily of the Valley, Lime tree flowers, Liquorice, Ma Huang, Male Fern, Mallow, Marigold, Marshmallow, Mate, Matricaria, Meadowsweet, Melilot, Melissa, Mistletoe, Motherwort, Muira puama, Myrrh, Nettle, Nux Vomica, 0- ak, Oats, Olive, Onion, Orange, Pansy, Passion Flower, Peppermint, Pick-tooth, Plantain, Pollen, Propolis, Pumpkin, Raspberry, Rest-Harrow, Rhubarb, Rosemary, Sage, Saw Palmetto, Senega, Senna, Shepherds Purse, Siberian Ginseng, Silverweed, St Johns Wort, St. Ma¬ rys Thistle, Thyme, Tormentil, Trefoil, Turmeric, Uva Ursi, Valerian, Wild Lettuce, Willow, Witch Hazel, Wormwood, Yarrow, Yohimbe, etc.
In the experimental section several examples are pre¬ sented which illustrate that it is possible to make successful compositions by the use according to the invention with substances ranging from a heavy and very lipophilic substance like coenzyme QIO to a more hydrophilic substance like aspirin. The preferred drug for the use according to the invention is a relatively lipophilic substance.
At least one and preferably two or more different es¬ ters of polyhydric alcohols having 2-8 carbon atoms, said esters containing at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or un¬ saturated fatty acid moiety of 4-30 carbon atoms, and preferably 8-22 carbon atoms.
The alcohol of the ester may for example be selected among polyhydric hydroxyalkanes having 2-4 carbon at¬ oms, i.e. 1, 2-ethanediol (ethylene glycol)
1,2-propanediol (propylene glycol)
1, 3-propanediol
1,2 , 3-propanetriol (glycerol)
1 ,2-butanediol 1, 3-butanediol 1 ,4-butanediol 1,2, 3-butanetriol 1,2,4-butanetriol and 1,2, 3,4-butanetetraol .
The alcohol of the ester may for example also be se¬ lected among monosaccharides and their corresponding sugar alcohols and desoxy sugars, preferably among pentoses and hexoses and their corresponding sugar al¬ cohols and desoxy sugars.
Examples of esters of monosaccharides and sugar alco¬ hols are acetylated fatty acid esters of sorbitol (e*9* acetylated sorbitan monooleate) or acetylated fatty acid esters of glucose.
Examples of esters of polyhydric hydroxyalkanes are esters of 1, 2-ethanediol (ethylene glycol), 1,2- propanediol (propylene glycol) or 1,2, 3-propanetriol (glycerol) which are preferred due to their well known low toxicity. In this respect esters having an acetic acid moiety (2:0) as the short chain are also espe¬ cially preferred. As illustrated in the experimental section these esters are expected to have a broad range of applications.
In Examples 1-10 successful formulations are accom¬ plished with esters of 1,2, 3-propanetriol (glycerol) having one or two acetic acid (2:0) moieties as short chains and one of the following fatty acids as the long chain: caprylic acid (8:0), capric acid (10:0), lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), linolic acid (18:2) or linolenic acid (18:3).
In examples 11-15 successful formulations are accom¬ plished with esters of sorbitol having acetic acid (2:0) moieties as short chains and oleic acid (18:1) or stearic acid (18:0) moieties as the long chain.
Optionally the composition may contain additives such as surfactants, solvents, thickeners, stabilisers, preservatives, antioxidants, flavour etc. to obtain a desirable product formulation. There are no limita¬ tions to the dosage form of the formulation but tab¬ lets, gelatine capsules, fluids or granulates are en¬ visaged.
In Examples 3 and 10 a surfactant (Polysorbate 80) is incorporated to obtain a desirable product formula¬ tion.
The ratio between the mixed-chainlength-esters and the drug of the composition would typically be 1-75 % drug and 25-99 % mixed-chainlength-esters by weight.
The pharmaceutical composition can be prepared by the use of the invention in several ways depending on the drug.
The mixed-chainlength-esters provide the convenience that they can be prepared especially to suit different drugs so that a high solubility of the drug in the mixed- chainlength-esters can be accomplished resulting in a high possible dosage of the drug.
In some cases the drug and the mixed-chainlength-esters can be mixed without employing an organic solvent. How- ever, in many cases the basic mixture of the drug and the mixed-chainlength-ester is more easily prepared by dis¬ solving the drug in an appropriate organic solvent, mix¬ ing it with the mixed-chainlength-ester(s) and subse¬ quently removing the solvent by evaporation.
In some cases it is advantageous or necessary to incorpo¬ rate surfactants or stabilisers to obtain a workable and stable composition. It is obvious to the person skilled in the art that the qualities of the composition may be varied by varying the mixed-chainlength-esters. It is also obvious to the skilled person that the employed additives may influence certain characteristics of the composition. For instance the rate of release and dispersion of the formulation in the digestive system can be increased by incorporating appropriate surfactants, such as bile salts, polyoxyeth¬ ylene glycolated vegetable oils (e.g. Cre aphor) or polyoxyethylene-sorbitan-fatty acid esters (e.g. Polysor¬ bate) .
Further, it is obvious to the skilled person that numer¬ ous different additives, for example solvents, preserva- tives, antioxidants, thickeners, colourings , etc. may be employed to obtain a suitable product for oral admini¬ stration. The composition can be administered orally in any form, for example in tablets, capsules, powders or as a liquid.
EXAMPLES
Example 1 (Progesterone mixed-chainlength-esters composi¬ tion) .
•a
5,00 g of progesterone (some of which was tagged with H) was added to 20,00 g of a mixture of mixed-chainlength- esters of 1,2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composi¬ tion in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
The composition was gently stirred and briefly heated to 90 °C. Ethanol was employed as a solvent.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
For the following pharmacokinetic study a reference preparation was made by the above procedure replacing mixed-chainlength-esters with peanut oil.
The radioactivity of both preparations was 27 μCi/g.
Pharmacokinetics in the rat.
Two groups of each 12 male Wistar rats were fasted for 12 hours and thereafter orally given corresponding to 230 mg progesterone kg" of the mixed-chainlength-esters formu¬ lation or the peanut oil formulation.
After 30, 60, 180 and 480 minutes 3 rats from each group were sacrificed and the blood collected. The blood was subjected to centrifugation and the plasma collected.
1 ml of plasma was mixed with 10 ml of scintillation cocktail and counted for 5 minutes.
The results are presented in figure 1 (time/plasma con¬ centration curve) where each point in the graph is the mean of 3 rats in counts per minute/ml.
The results clearly indicate that the mixed-chainlength- esters (MCE) result in an improved oral bioavailability of progesterone compared to the peanut oil formulation. This is interesting since a dispersion in vegetable oil is the preferred known oral preparation of progesterone. The bioavailability of the mixed-chainlength-esters for¬ mulation was 23,2 % better than the peanut oil formula¬ tion measured as the area under the time/plasma concen¬ tration curve (AUC) .
Example 2 (Retinol mixed-chainlength-esters composition) .
3 0,250 g of retinol (some of which was tagged with H) was added to 4,750 g of a mixture of mixed-chainlength-esters of 1,2 , 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 10 % palmitic (16:0), 10 % stearic acid (18:0), 70 % oleic acid (18:l)and 10 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety¬ lated and 10 % were monoacetylated.
The composition was gently stirred at 60 °C.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
For the following pharmacokinetic study a reference preparation was made by the above procedure replacing mixed-chainlength-esters with peanut oil .
The radioactivity of both preparations was 27 μCi/g.
Pharmacokinetics in the rat.
Two groups of each 12 male Wistar rats were fasted for 12 hours and thereafter orally given corresponding to 70 mg retinol kg" of the mixed-chainlength-esters formulation or the peanut oil formulation. After 30, 60, 180 and 480 minutes 3 rats from each group were sacrificed and the blood collected. The blood was subjected to centrifugation and the plasma collected.
1 ml of plasma was mixed with 10 ml of scintillation cocktail and counted for 5 minutes.
The results are presented in figure 2 (time/plasma con¬ centration curve) where each point in the graph is the mean of 3 rats in counts per minute/ml .
The results clearly indicate that the mixed-chainlength- esters (MCE) result in an improved oral bioavailability of retinol compared to the peanut oil formulation.
The bioavailability of the mixed-chainlength-esters for¬ mulation was 33,9 % better than the peanut oil formula¬ tion measured as the AUC.
Example 3 (Acyclovir mixed-chainlength-esters composi¬ tion) .
5,00 g of acyclovir was added to 20,00 g of a mixture of mixed-chainlength-esters of 1,2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety- lated and 10 % were monoacetylated.
0,25 g of Polysorbate 80 was added and the mixture was stirred vigorously and heated briefly to 90 °C . Ethanol was employed as a solvent. The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 4 (α-tocopherol mixed-chainlength-esters composi¬ tion) .
5,00 g of dl-α-tocopherol was added to 10,00 g of a mix¬ ture of mixed-chainlength-esters of 1, 2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 10 % palmitic (16:0), 10 % stearic acid (18:0), 70 % oleic acid (18:1) and 10 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
The composition was gently stirred at 60 °C.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 5 (Ibuprofen mixed-chainlength-esters composi¬ tion) .
5,00 g of ibuprofen was added to 5,00 g of a mixture of mixed-chainlength-esters of 1,2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety¬ lated and 10 % were monoacetylated.
The composition was gently stirred at 60 °C.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
The composition was stored for 12 weeks at 0-5 °C and no precipitation of ibuprofen occurred.
Example 6 (aspirin mixed-chainlength-esters composition)
5,00 g of aspirin was added to 15,00 g of a mixture of mixed-chainlength-esters of 1,2 , 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety¬ lated and 10 % were monoacetylated.
The composition was vigorously stirred at 90 °C
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 7 (Coenzyme Q10 mixed-chainlength-esters composi¬ tion) . 2,00 g of coenzyme QIO was added to 8,00 g of a mixture of mixed-chainlength-esters of 1, 2, 3-propanetriol (glyce¬ rol) with acetic acid (2:0) as the short chain and one of the following fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % capric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approximately 90 % of the monoglycerides were diacety¬ lated and 10 % were monoacetylated.
The composition was gently stirred at 60 C.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
The composition was filled in hard gelatine capsules (0,5 ml) and stored for 12 months at room temperature (20-25 C). The composition was found to be stable and no pre¬ cipitation of coenzyme Q10 was observed as evaluated by microscopy (400-900 x magnification with phase contrast).
Human pharmacokinetics.
For the following pharmacokinetic study a reference pre¬ paration was made by the above procedure replacing mixed- chainlength-esters with soybean oil.
Two human subjects were fasted for 12 hours and thereaf¬ ter given corresponding to 100 mg coenzyme Q10 of the mixed-chainlength-esters formulation or the soybean oil formulation with a standard meal.
Each formulation was given on an individual day. Blood samples were collected after 0, 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours. The blood was subjected to centrifuga¬ tion and the plasma collected. The plasma samples were analysed by reversed phase HPLC and the quantity of coenzyme QIO was determined. The re¬ sults are presented in figure 3 (time/plasma concentra¬ tion curve) where each point in the graph is the mean of two persons .
The results clearly indicate that the mixed-chainlength- esters (MCE) result in an improved oral bioavailability of coenzyme QIO compared to the soybean oil formulation.
The bioavailability of the mixed-chainlength-esters for¬ mulation was 71,4 % better than that of the soybean oil formulation measured as the AUC.
Example 8 (Ginkgo biloba mixed-chainlength-esters compo¬ sition) .
5,00 g of Ginkgo biloba extract (dry residue of alcoholic extract) was added to 20,00 g of a mixture of mixed- chainlength-esters of 1,2,3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the fol¬ lowing fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % ca¬ pric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approxi¬ mately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
The composition was gently stirred at 60 °C. Ethanol was used as a solvent and was subsequently removed by evapo¬ ration.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature. Example 9 (Ginger mixed-chainlength-esters composition).
10,00 g of Ginger extract (dry residue of alcoholic ex¬ tract) was added to 10,00 g of a mixture of mixed- chainlength-esters of 1, 2 , 3-proρanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the fol¬ lowing fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % ca¬ pric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0) 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approxi¬ mately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
The composition was gently stirred at 60 °C .
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Human pharmacokinetics.
For the following pharmacokinetic study a reference pre¬ paration was made by the above procedure replacing mixed- chainlenght-esters with soybean oil .
Two human subjects were fasted for 12 hours and thereaf- ter given 500 mg of the mixed-chainlength-esters formula¬ tion or the medium chain triglyceride formulation with a standard meal.
Each formulation was given on an individual day. Blood samples were collected after 30, 60, 90, 120, 150, 180, 240 and 300 minutes. The blood was subjected to centrifu¬ gation and the plasma collected. The plasma samples were analysed by reversed phase HPLC and the quantity of gingerdione a major active component of ginger extract was determined. The results are pre¬ sented in figure 4 (time/plasma concentration curve), where each point in the graph is the mean of two persons .
The results clearly indicate that the mixed-chainlength- esters (MCE) result in an improved oral bioavailability of gingerdione compared to the soybean oil formulation.
The bioavailability of the mixed-chainlength-esters for¬ mulation was 120,9 % better than that of the soybean oil formulation measured as the AUC.
Example 10 (Echinacea mixed-chainlength-esters composi¬ tion) .
5,00 g of Echinacea extract (dry residue of hydroalco¬ holic extract) was added to 5,00 g of a mixture of mixed- chainlength-esters of 1, 2, 3-propanetriol (glycerol) with acetic acid (2:0) as the short chain and one of the fol¬ lowing fatty acids as the long chain (approximate fatty acid composition in %): 5 % caprylic acid (8:0), 5 % ca¬ pric acid (10:0), 50 % lauric acid (12:0), 20 % myristic acid (14:0), 10 % palmitic acid (16:0), 5 % oleic acid (18:1) and 5 % linoleic acid (18:2) as the long chain. The mixed-chainlength-esters were prepared by reacting fatty acid monoglycerides with acetic anhydride. Approxi¬ mately 90 % of the monoglycerides were diacetylated and 10 % were monoacetylated.
0,2 g of Polysorbate 80 was added along with 5 ml of wa¬ ter and the mixture was stirred vigorously without heat¬ ing. When a homogeneous mixture was accomplished the wa- ter was removed by evaporation under vacuum. The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 11 (Coenzyme Q10 mixed-chainlength-esters compo¬ sition) .
2,5 g of coenzyme Q10 was added to 7,5 g of acetylated sorbitan monooleate. The mixed-chainlength-ester was pre- pared by reacting sorbitan monooleate with acetic anhy¬ dride.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo- geneous and stable at room temperature.
Example 12 (Garlic mixed-chainlength-esters composition).
4,0 g of Garlic extract (dry residue of alcoholic ex- tract) was added to 6,0 g of a mixture of acetylated sor¬ bitan monostearate (10 %) and acetylated sorbitan monoo¬ leate (90 %). The mixed-chainlength-esters were prepared by reacting the sorbitan monoesters with acetic anhy¬ dride.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 13 (Propolis mixed-chainlength-ester composition)
5,0 g of Propolis extract (dry residue of alcoholic ex¬ tract) was added to 5,0 g of a mixture of acetylated sor¬ bitan monostearate (10 %) and acetylated sorbitan monoo- leate (90 %). The mixed-chainlength-esters were prepared by reacting the sorbitan monoesters with acetic anhy¬ dride. The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 14 (Parthenium integrifolium mixed-chainlength- ester composition)
7,0 g of Parthenium integrifolium extract (dry residue of alcoholic extract) was added to 3,0 g of acetylated sor- bitan monooleate. The mixed-chainlength-ester was pre¬ pared by reacting sorbitan monooleate with acetic anhy¬ dride.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.
Example 15 (Tocopheryl acetate mixed-chainlength-ester composition)
5,0 g of tocopheryl acetate was added to 5,0 g of acety¬ lated sorbitan monooleate. The mixed-chainlength-ester was prepared by reacting sorbitan monooleate with acetic anhydride.
The composition was evaluated by microscopy (400-900 x magnification with phase contrast) and found to be homo¬ geneous and stable at room temperature.

Claims

PATENT CLAIMS
1. Use of an ester of a polyhydric alcohol having 2-8 carbon atoms, said ester containing at least one fatty acid moiety of 1-3 carbon atoms and at least one satu¬ rated or unsaturated fatty acid moiety of 4-30 carbon at¬ oms, for the preparation of a pharmaceutical composition comprising at least one drug substance and at least one such ester and having enhanced oral bioavailability of said drug substance.
2. Use according to claim 1, wherein the polyhydric alco¬ hol is selected from the group consisting of polyhydric hydroxyalkanes having 2-4 carbon atoms .
3. Use according to claim 1, wherein the polyhydric alco¬ hol is selected from the group consisting of monosaccha¬ rides and their corresponding sugar alcohols and desoxy sugars .
4. Use according to claim 3, wherein the polyhydric alco¬ hol is selected from the group consisting of pentoses and hexoses and their corresponding sugar alcohols and desoxy sugars .
5. Use according to claim 4, wherein the polyhydric alco¬ hol is glucose or sorbitol .
6. Use according to any one of the preceding claims, wherein the fatty acid moiety of 1-3 carbon atoms is ace¬ tyl.
7. Use according to any one of the preceding claims, wherein the fatty acid moiety of 4-30 carbon atoms is a moiety of 8-22 carbon atoms.
8. Use according to claim 7, wherein the fatty acid moi¬ ety of 8-22 carbon atoms is selected from the group con- sisting of octanoyl, decanoyl, lauroyl, myristoyl, palmi¬ toyl, stearoyl, oleoyl, linoloyl and linolenoyl.
9. Use according to claim 1, wherein said ester is an acetylated glycerol or sorbitan monoester having a fatty acid moiety of 4-30 carbon atoms.
10. Use according to any one of the preceding claims, which comprises two or more of said esters.
11. A method of enhancing the oral bioavailability of drug substances which comprises admixing with a drug sub¬ stance or drug formulation at least one ester of a poly¬ hydric alcohol having 2-8 carbon atoms, said ester con- taining at least one fatty acid moiety of 1-3 carbon at¬ oms and at least one saturated or unsaturated fatty acid moiety of 4-30 carbon atoms.
12. A method according to claim 11, wherein the polyhy- dric alcohol is selected from the group consisting of po¬ lyhydric hydroxyalkanes having 2-4 carbon atoms.
13. A method according to claim 11, wherein the polyhy¬ dric alcohol is selected from the group consisting of monosaccharides and their corresponding sugar alcohols and desoxy sugars .
14 A method according to claim 13, wherein the polyhydric alcohol is selected from the group consisting of pentoses and hexoses and their corresponding sugar alcohols and desoxy sugars .
15. A method according to claim 14, wherein the polyhy¬ dric alcohol is glucose or sorbitol
16. A method according to any one of claims 11-15, wherein the fatty acid moiety of 1-3 carbon atoms is ace- tyl.
17. A method according to any one of claims 11-16, wherein the fatty acid moiety of 4-30 carbon atoms is a moiety of 8-22 carbon atoms.
18 A method according to claim 17, wherein the fatty acid moiety of 8-22 carbon atoms is selected from the group consisting of octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl, linoloyl and linolenoyl.
19. A method according to claim 11, wherein said ester is an acetylated glycerol or sorbitan monoester having a fatty acid moiety of 4-30 carbon atoms.
20. A method according to any one of claims 11-19, wherein the drug substance or drug formulation is admixed with two or more of said esters .
21. A method according to any one of claims 11-20, wherein the mixing of the drug and the ester(s) is car- ried out in an organic solvent which is afterwards dis¬ tilled off.
22. An ester of a polyhydric alcohol having 2-8 carbon atoms, except glycerol, said ester containing at least one fatty acid moiety of 1-3 carbon atoms and at least one saturated or unsaturated fatty acid moiety of 4-30 carbon atoms .
23. An ester according to claim 22, wherein the polyhy- dric alcohol is selected from the group consisting of po¬ lyhydric hydroxyalkanes having 2-4 carbon atoms, except glycerol .
24. An ester according to claim 22, wherein the polyhy- dric alcohol is selected from the group consisting of monosaccharides and their corresponding sugar alcohols and desoxy sugars, except glycerol.
25 An ester according to claim 24, wherein the polyhydric alkohol is selected from the group consisting of pentoses and hexoses and their corresponding sugar alcohols and desoxy sugars .
26. An ester according to claim 25, wherein the polyhy¬ dric alcohol is glucose or sorbitol
27. An ester according to any one of claims 22-26, wherein the fatty acid moiety of 1-3 carbon atoms is ace¬ tyl.
28. An ester according to any one of claims 22-27, wherein the fatty acid moiety of 4-30 carbon atoms is a moiety of 8-22 carbon atoms.
29. An ester according to claim 28, wherein the fatty acid moiety of 8-22 carbon atoms is selected from the group consisting of octanoyl, decanoyl, lauroyl, yris- toyl, palmitoyl, stearoyl, oleoyl, linoloyl and linole- noyl .
30. A pharmaceutical composition comprising at least one drug substance and at least one ester according to any one of claims 22-29.
PCT/DK1996/000387 1995-09-13 1996-09-13 Use of esters of polyhydric alcohols to enhance the oral bioavailability of drug substances as well as novel esters and pharmaceutical compositions containing them WO1997009978A1 (en)

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RU2251415C2 (en) * 1999-03-10 2005-05-10 Аванир Фармасьютикэлз Synergistic inhibition of viral replication with long-chain hydrocarbons and nucleoside analogs
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