A PHARMACEUTICAL COMPOSITION WITH IMPROVED BIOAVAILABILITY OF INOSITOL PHOSPHATE

Abstract: The invention relates to an inositol phosphate containing pharmaceutical composition which comprises a nitrogen-containing compound for improvement of the bioavailability of the inositol phosphate in mammals including man at non-parenteral administration. The invention also covers the use of at least one nitrogen-containing compound for the preparing of an inositol phosphate containing medicament with improved bioavailibility of inositol phosphate in mammals including man at non-parenteral administration.

Description: Δ pharmaceutical composition with improved bioavailability of inositol phosphate The present invention relates to an inositol phosphate containing pharmaceu¬ tical composition with improved bioavailability of inositol phosphate and the use of at least one nitrogen-containing compound for the preparing of an inositol phosphate containing medicament -with improved bioavailability of inositol phosphate. Hydrophilic and ionized drugs most often encounter rather poor penetration of the epithelial barriers to the capillaries of the portal circulation as most of this type of substances are transported by passive diffusion. Inositol phosphates belong to this group. Normally it is the unionized fraction of the drug that partition across the lipid membranes and this fraction is most often small over the pH-range encoun¬ tered in the gastrointestinal tract. It is known from the literature, for example Jonkman J.H.G. and Hunt CA. (1983) Pharmaceutische Weekblad Scientific Edition 5, 41-48. that a combi¬ nation of a quartemary ammonium compound and sulfonic acids are absor¬ bed to a small extent after oral administration. The absorption is described as poor and in many cases contradictory. In the literature nothing has been described about the use of counter ions such as nitrogen-containing compounds together with inositol phosphates for improvement of the bioavailability. At oral administration the properties of inositol phosphates per se result in limitations in respect of the uptake of the compounds from the intestine. In order to optimize the effect of these substances in the body it is desirable that as large a portion as possible of the added amount can be utilized effectively. Thereby the added amount can be reduced which is advantageous for the patient for example when the drug D-myo-inositol-l,2,6-trisphosphate QP3) is used. According to the present invention it has now quite surprisingly been possible to meet the above desire and bring about an inositol phosphate containing pharmaceutical composition which comprises a nitrogen-containing com¬ pound for improvement of the bioavailability of the inositol phosphate in mammals including man at non-parenteral administration. The expression bioavailability stands for a measurement of how large a por¬ tion of an administrated drug that occurs in the blood stream when the way of administration of the drug is non-parenteral. The term thus shows the amount of the drug that has been able to penetrate membrane barriers after for example oral administration, topical administration or intraperitoneal administration. The nitrogen-containing compound can be for example a quartemary ammo¬ nium ion, a tertiary amine, a diamine. a polyamine. an amino acid or a deri¬ vative thereof. The quartemary ammonium ions used according to the invention is defined as follows: 1. ÷ N(RιR2 R 3 R 4- wherein R^, R2. R3 and R4 independently are (i) hydrogen (ii) a straight or branched alkyl with 1 to 24 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl. octyl, nonyl, decyl, undecyl, dodecyl, tridecyl. tetradecyl. pentadecyl. hexadecyl, hepta- decyl, octadecyl, eicosyl and docosyl; (ill) cycloalkyl with 3 to 16 carbon atoms such as cyclopropyl, cyclopen- tyl and cyclohexyl; (iv) alkenyl with 2 to 24 carbon atoms such as vinyl, allyl, propenyl, octadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl and arachidonyl; (v) cycloalkenyl with 5 to 16 carbon atoms such as cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl; (vi) aryl with 6 to 24 carbon atoms such as phenyl and biphenyl; ( ii) aralkyl, alkaryl, aralkenyl, alkenylaryl wherein alkyl, aryl and alkenyl are as previously defined. The above groups (ϋ) to (vii) are unsubstituted or substituted with hydroxy; oxo; alkoxy; aryloxy; carboxy; esterified carboxy; amino; substituted amino; formyl; acyl; acyloxy; or acylamine. Preferred nitrogen-containing compounds in this group according to the invention are N-tetramethylammonium, N-tetraethylammonium, N-tetrapro- pylammonium, N-tetrabutylammonium, N-tetrapenrylammonium, N-tetra- hexylammonium, N-tetraheptylammonium and N-tetraoctylammonium. Other preferred nitrogen-containing compounds are N-decyltrimethylammonium, N- undecyltrimethylammor um, N-dodecyltrimethylammonium, N-tridecyltrimethylammonium, N-tetradecyltrimethylammonoum. N-pentadecyltrimethylammonium, N-hexadecyltrimethylammonium, N-benzyltrimethylamπionium. 2. + N(RιR2R3)R5 wherein Rj, R2, R3 are as defined above and preferably methyl, ethyl or propyl and wherein R5 is (i) -(CH^nOCOR β wherein n > 2 and wherein RQ is a straight or branched alkyl or alkenyl with 1 to 24 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl. dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl. eicosyl. docosyl, vinyl, allyl, octadienyl. octenyl, decenyl, dodecenyl, tetradecenyl. hexadecenyl, octadecenyl. octadecadienyl. nonadecenyl, octadecatrienyl and/or arachidonyl or where Rg is -CH 2 CH(CH 3 )OCOR 1 . -CH[CH3)CH 2 OCOR 1 . -CH 2 CH(OCOR 1 )CH 2 OCOR 1 . -CH 2 CH(OH)CH 2 OCOR 1 . -CH2CH(CH 2 OH)OCORι . -CH[CH2OH)CH 2 OCOR 1 or -CH(CH 3 )COORι wherein R x is as de¬ fined above. (ϋ) -(CH2) n OR Q wherein n and R are as defined above. Preferred nitrogen-containing coumpounds in this group according to the invention are N-deranoyloxypropyltrimethyla_mmonium, N-undecanoyl- oxypropyltrimethylammonium, N-dodecanoyloxypropyltrimethyl- ammonium, N-tridecanoyloxypropyltrimethylamm.oniuιn. N-tetra- decanoyloxypropyltriπiethylammonium. N-pentadecanoyloxy- propyltrimefhyl ammoniu . N-hexadecanoyloxypropyl trimiethylam onium. N-decanoyloxyethyltrimethylammoniuπi, N-undec^noyloxyel±iyltrimethylammonium. N-dodecanoyloxy ethyltrimethylammonium. N-Mdecanoyloxyethyltrimethylammonium. N- tetiadecanoyloxyethyltriπiethylammoniuπi. N-pentadecanoyloxy- ethyltrimethyl-ammonium. N-hexadecanoyloxyethyltrimethylammonium. N-decyloxypropyltrimethylammomum, N-undecyloxypropyltri- methylammonium, N-dodecyloxypropyltrimethylammonium, N- todecyloxypropyltri_methylamιnonium. N-tetradecyloxypropyl- trimethylammonium, N-pentadecyloxypro^yltrimethylammonium. N- hexadecyloxypropyltrimethylammonium, N-decyloxyethyltri- methylammonium. N-undecyloxyethyltri_methylaιmnoιιluιn. N-dodeqrloxyethyltrimethylamm.onium. N-tridecylόxyethyltri- methylammonium, N-te1τadecyloxyethyltrimethylammonium. N- pentadecyloxyethyltrimethylammomum, N-hexadecyloxytri- methylammonium. (iϋ) -(C(Ry)2) n COOR6 wherein n > 1 and wherein Ry is hydrogen and/or lower straight or branched alkyl such as methyl, ethyl, propyl, and/or butyl and wherein RQ is as defined above. Preferably n=l and R Q is hexyl, heptyl. octyl, nonyl. decyl, dodecyl, tridecyl. tetradecyl. pentadecyl or hexadecyl. (iv) -C(R )2OCOR Q wherein Ry is hydrogen and/or lower straight or branched alkyl such as methyl, ethyl, propyl and/or butyl and wherein Rg is as defined above. Preferably RQ is hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl. (v) -(C(Ry)2) n ( c ( R 8)2)m COOR 6 wherein n > 1, m > 1 and wherein Ry is as defined above, wherein RQ is hydrogen, hydroxyl, alkyloxy or acyloxy and wherein Rg is as defined above. Preferably the com¬ pounds are selected from the following group: + N(CH3) 3 CH 2 CHOHCH2COOR 6 wherein Re is hexyl. heptyl. octyl. nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl; + N(CH3)3CH2CHOR9CH2COOR6 wherein RQ is as defined above and wherein Rø is lower alkyl such as methyl, ethyl and propyl or lower acyl such as formyl, acetyl or propionyl. (vi) -C(Ry)2) n CONR 7 CRyCOORι wherein n > 1 and wherein Ry is hy¬ drogen and/ or lower straight or branched alkyl such as methyl, ethyl, propyl and /or butyl and wherein R is as defined above. Pref¬ erably n = 1 and Ry is hydrogen. e embodiment of this type of the invention R ] _, R2 and/or R3 are i) hydrogen; ϋ) a straight or branched alkyl selected from the group of methyl, ethyl, propyl. butyl, pentyl, hexyl, heptyl and/or octyl; and Rs is -(CH2)OCOR5 wherein RQ is selected from the group of hexyl, heptyl. octyl, nonyl, decyl, dodecyl, tridecyl. tetradecyl. pentadecyl and/or hexadecyl. In another embodiment of the invention Rj_, R2 and/or R3 are i) hydrogen; ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/ or octyl; and R5 is CU2)O Q wherein RQ is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl. pentadecyl and/or hexadecyl. In another embodiment of the invention R » R2 and/or R3 are i) hydrogen: ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/or octyl; and R5 is -CCRy)2 COORg wherein RQ is selected from the group, of hexyl, heptyl, octyl. nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/ or hexadecyl or from the group of -CH2CH(CH3)OCOR 1 , -CHCCH 3 )CH 2 OCOR 1 . -CH 2 CH(OCOR 1 )CH 2 OCOR 1 , -CH(CH 2 OCOR 1 ) 2 , -CH 2 CH(OH)CH 2 OCOR 1 , -CH 2 CH(CH 2 OH)OCOR 1 . -CH(CH 2 OH)CH 2 OCOR 1 or -CH(CH3)COOR! and wherein Ry is i) hydrogen; ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl and/or butyl; In still another preferred embodiment of the invention R * -_, R2 and/or R3 are i) hydrogen; ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/or octyl; and R5 is -C(R )2OCOR6 wherein Rg is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/ or hexadecyl and wherein Ry is i) hydrogen; ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and /or octyl; 3. A heterocyclic group containing at least one nitrogen atom such as C5H R1 QNRI 1 wherein R * Q is hydrogen, lower alkyl, carboxy, esterified carboxy or carboxamide and wherein R j is (i) Rj as defined above (ii) -(C(Ry)2)r** CORg wherein n > 1 and wherein Ry is hydrogen or lower alkyl such as methyl, ethyl, propyl and /or butyl and Rg is as defined above. Preferred nitrogen-containing compounds are l-methyl-2-pyridIne amide, l-ethyl-2-pyridine amide, l-propyl-2-pyridine amide, 1- methyl-3-pyridine amide, l- " ethyl-3-pyridine amide, l-propyl-3- pyridine amide, l-methyl-4-pyridine amide, l-ethyl-4-pyridine amide, l-propyl-4-pyridine amide. Other preferred nitrogen-containing compounds are where n = 1, Ry is hydrogen and Rg is hexyl. heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl. The tertiary amines used according to the invention are: (1) N(R R2R3) wherein Rγ, R and R3 independently are as defined above. Preferred nitrogen-containing compounds according to this type of the invention are octyldimethyl amine, nonyldimethyl amine. decyldimethyl amine, undecyldimethyl amine. dodecyldimethyl amine, tridecyldimethyl amine, tetradecyldimethyl amine. pentadecyldimethyl amine or hexadecyldimethyl amine. (2) A heterocylic group containing at least one nitrogen atom such as C5H5RX0N wherein R^ Q is hydrogen, lower alkyl, carboxy, esterified carboxy or carboxamide. Preferred nitrogen-containing compounds are 2-pyridine amide, 3- pyridine amide and 4-pyridine amide. Other amines are also to be contemplated to be in the scope of the invention. These include for example diamines and polyamines such as alkyllysine, alkylarginine, alkylhistidine and guanidin or derivatives thereof. Preferred compounds according to this embodiment of the invention are ethyllysine. propyllysine, butyEysine, ethylarginine, propylarginine, butylar- ginine, ethylhistidjne, propvlhistidine and butylhistidine. Other nitrogen-containing compounds within the scope of the invention are amino acids such as arginine, lysine, histidine, creatinine or their derivatives and polyamino acids such as polylysine and polyornithine. StiE other nitrogen-containing compounds related to the invention are cationic polymers such as aminopolysaccharides. When the nitrogen-containing compound is a quartemary ammonium ion an ion-pair structure can be formed between the compound and inositol phos¬ phate. This can also be the case for other nitrogen-containing compounds when they are protonated depending on the pH. An ion-pair structure is a non-covalent interaction example between one or more quartemary ammonium ions and one or more inositol phosphates, as described in the foEowing figure: [IP 3 ](6-rι)- [N(R 1 R 2 R3R4)] n I1+ The expression inositol phosphate comprises different isomers of inositol for example myo-inositol, aEo-inositol, cis-inositol, chiro-inositol. scyEo-inositol, muco-inositol, neo-inositol or epi-inositol. Most often the inositol isomer is myo-inositol. The degree of phosphorylation can vary between one phosphate group/inositol moiety to six phosphate groups/inositol moiety. Preferably inositol trisphosphate isomers are used according to the invention and most preferably D-myo-inositol-1.2.6-trisphosphate (IP3) is used. According to the invention the inositol phosphate is most often present in a salt form or in a form where only a few of the negative charges are protonated. The salt can contain one or more cations in different combinations. Examples of cations are sodium and potassium ions. When the ion-pair structure is formed with a nitrogen-containing compound such as a quarternary ammo¬ nium ion one or more of the protons and cations wiE be replaced with the quarternary ammonium ions. The pharmaceutical composition according to the invention may be adminis¬ tered oraEy, topicaEy, rectaEy or .by inhalation spray in dosage forms or for¬ mulations comprising conventional, non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The pharmaceutical composition for oral use can be present in different forms such as capsules, granules, tablets, troches, lozenges, aqueous suspensions, dispensible powders, emulsions, syrups or elixirs. When the composition is present in Equid form capsules are preferably utilized. At the use of granules, these preferably have a size of 0.15 - 2 mm. Either the granules can consist of the pharmaceutical composition per se or of the composition and suitable fiEers. When the pharmaceutical composition is used in a tablet form, the tablets can have a weight of 50 - 1500 mg, for example preferably 50 - 800 mg and most preferably 100 - 500 mg. Formulations for oral use include tablets which contain the active ingredient in a mixture with non-toxic pharmaceuticaEy acceptable excipients. These excipients may be, for example, inert dEuents, such as calcium carbonate, sodiu chloride, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, potato starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert soEd dEuent, for example, calciu carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oE medium, for ex¬ ample, peanut oE, Equid paraffin, or oEve oE. For the rectal appEcation of the compositin of this invention, typical dosage forms include suppositories, rectal gelatin capsules (solutions and suspen¬ sions), and enemas or micro-enemas (solutions and suspensions). Thus, in a typical suppository formiEation, any one of the compounds of this invention is combined with any pharmaceuticaEy acceptable suppository base such as co¬ coa butter, esterified fatty acids, glycerinated gelatin, and various water- soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid ester. Various additives like saEcylates or surfactant mate¬ rials may be incorporated. For topical use, creams, ointments, gels, solutions or the Eke containing the compositions are employed according to methods recognized in the art. Naturally, therapeutic dosage range for the compounds of the present inven¬ tion wEl vary with the size and needs of the patient and the particular pain or disease symptom being treated. The administration of the pharmaceutical composition according to the inven¬ tion can be in a combined dosage form or in separate dosage forms. As mentioned above the invention also relates to the use of at least one nitro¬ gen-containing compound for the preparing of an inositol phosphate contain¬ ing medicament with improved bioavaEabEity of inositol phosphate in mam¬ mals including man at non-parenteral administration. The nitrogen-containing compound can be a quarternary ammonium com¬ pound, a tertiary amine, a diamine, a polyamine, an amino acid or a deriva¬ tive thereof as defined above. Preferably the inositol phosphate is inositol trisphosphate and most preferably the inositol trisphospate is D-myo-inositol- 1.2.6-trisphosphate. Another embodiment of the invention relates to pharmaceutical compositions comprising a nitrogen- containing compound and other phosphorus-containing inositol derivatives. For example different types of phosphonates of inositol encounter the need of improved bioavaEabEity after non-parenteral administ¬ ration. StiE another embodiment of the invention relates to pharmaceutical compositions comprising a nitrogen- containing compound and derivatives of inositol phosphates and inositol phosphonates. The derivatives could be com- pounds where the phosphate or phosphonate group or groups are further es¬ terified or compounds where the hydroxyl groups on the inositol moiety are etherified or esterfied, such as alkanoyl and carbamoyl derivatives. A further embodiment of the invention is related to compositions comprising a nitrogen- containing compound and inositol derivatized with other charged groups such as carboxyl and sulphonyl. The nitrogen-containing compounds used in these embodiments belong to the same groups as disclosed above. The invention also relates to the improvement of the penetration of cellmem- branes in a wider aspect than in the above definition of biovaEabEity. Under certain circumstances there is a need to be able to obtain an improved abEity of different isomers of inositol phosphates or derivatives thereof to cross ceE membranes . Such an example is when it is desirable to let the inositol phosphate or its derivative influence different intraceEular metaboEc pathways. This can be the case for example when new drugs based on inositolphosphate compounds are being developed. Another example is when the knowledge of different ceEular signal systems is further explored. For example it is known that some iso- meric structures of inositol phosphates exist intracellularly. In many cases it is advantageous to be able to add these substances from the extraceEular space in order to clarify in more detaE how they effect the behaviour of the ceEs. This knowledge can then be used in order to develop agonistic or anta¬ gonistic compounds effecting the ceEular response. The combination of a nitrogen-containing compound such as a quarternary ammonium ion and an inositol phosphate or its derivative wEl facEitate the penetration across ceEular membranes. Another area is when it is desirable to facEitate the transport of nucleosides across ceEular membranes. The combination of a nitrogen-containing compound such as a quarternary ammonium ion and a nucleosϊde wEl enhance the penetration of ceEular membranes. Furthermore the invention can be used for other pharmaceuticals which suffer from low bioavaEabEity due to the same reasons as inositol phosphates and their derivatives. One such appEcation is a pharmaceutical composition com¬ prising a nitrogen-containing compound and a bisphosphonate or a derivative thereof useful for the treatment of bone disorders such as osteoporosis and other conditions characterized by abnormal calcium metaboEsm. The bisphosphonate or the derivative thereof could be selected from the group of hydroxy ethane bisphosphonate, amino ethane bisphosphonate, dichlo- romethylene bisphosphonate, methylene bisphosphonate, and preferably: l-hydroxy-3-aminopropane- 1 , 1 -bisphosphonate l-hydroxy-6-aminohexane- 1, 1 -bisphosphonate 4-amino- 1-hydroxybutyEdene- 1, 1-bisphonate N-methyl-4-amino- 1 -hydroxy butyEdene- 1 , 1 -bisphosphonate 3-amino- 1-hydroxypropyEdene- 1 , 1 -bisphosphonate 1-hydroxy ethyEdene-1, 1 -bisphosphonate 4-(hydroxy methylene-bisphosphonate)piperidine. Another appEcation is a pharmaceutical composition comprising a nitrogen- containing compound and a bisphosphonate or a derivative thereof useful for the treatment of cardiovascular conditions such as increased cholesterol lev¬ els and atherosclerosis. The bisphosphonate or the derivative thereof could be selected from the group of alkyl bisphosphonates, alkenyl bisphosphonates, alkynyl bisphosphonates, phenyl alkyl bisphosphonates and phenoxyalkyl bisphosphonates . StiE another appEcation is a pharmaceutical composition comprising a nitro¬ gen-containing compound and a. specific bisphosphonate useful as antimi¬ crobial agents. The bisphosphonate in this appEcation is selected from the group of alkyl ethenyEdene bisphosphonates such as tetraisopropyl ethenyEd- ene bisphosphonate and diethyl dibutyl ethenyEdene bisphosphonate. The in¬ vention can also be used for other pharmaceuticals suffering from low bioavaEabEity such as antiviral agents. One such appEcation is a pharma¬ ceutical composition comprising a nitrogen-containing compound and a charged phosphorus-containing pharmaceutical or a biologicaEy active compound such as: phosphonoformiate phosphonoacetate 3-azido thymidine-5-phosphate 9-(2-phosphonyl methoxy ethyl) adenine S-9-(3-hydroxy-2-ph_osphonyl methoxy propyl)-adenine/cytosine 2',3'-didehydro-2,3-dideoxy thymidine (2R, 5R)-9-(2,5-dihydro-5-phosphonomethoxy)-2-furanyl adenosine and de¬ rivatives thereof. The compositions are useful for the treatment of CMV-Infec- tions, HIV-infections, herpes simplex and hepatitis B. The invention can also be used for other pharmaceuticals and biologicaEy active compounds with low and Emited bioavaEabEity such as phosphoiylated and phosphonylated sugar residues, for example hydroxy phosphonyl glu- coseamine derivatives, purine and pyrimidine nucleotides and derivatives thereof for example 2'-deoxy-5-fluorouridine 5'-phosphate and oEgonucleo- tides and derivatives therof. Those skiEed in the art wEl realize that the Est of compounds is not exhaustive and the invention is also appEcable to other pharmaceuticals and biologicaEy active compounds comprising a phosphate or phosphonate moiety. The invention wEl be explained further in connection with the embodiment examples below, however without limiting it thereto. Example 1 shows the manufacturing of a pharmaceutical composition com¬ prising a quartemary ammoniu ion and IP3. Example 2 and 3 iEustrates the determination of the bioavaEabEity of two different quarternary ammonium ions and IP3 after oral administration whEe example 4 describes the bioavaE¬ abEity of a composition comprising a tertiary amine and IP3. Example 1 The pentasodium salt of D-myo-inositol-1.2.6-trisphosphate (LP3), 2.0 g, was converted to the acid form by a cation exchanger in acid form. To a concen¬ trated solution of the acid form of IP3 was added 3.7 g of N(3-dodecanoyl oxy)propyltrimethylammonium hydroxide to form an ion-pair structure con¬ sisting of 3 moles of the quarternary ammonium ion/IP3-moiety. Example 2 The bioavaEabEity of N(3-dodecanoyloxy)propyltrimet_hylammonium inositol trisphosphate (obtained according to Example 1) after oral administration was determined in an experiment with pigs. Five pigs were given an intravenous injection of the sodium salt of D-myo-inositol-1.2.6-trisphosphate (IP3) and blood samples were coEected 0.25 hr, 0.5 hr, 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs and 24 hrs after the injection. The blood samples were assayed for the content of IP3 and these measurements were used for the calculation of the reference da* a as 100 % of the substance is introduced into the blood stream after an int. venous injection. Another five pigs were given the N(3-dodecanoyloxy)propyltrimethyl ammo¬ nium salt of IP3 as an intraduodenal dosing. The animals were treated with Atropin® and anaesthetized with HypnodEO/Sedaperone® whereafter a lapa- rotomy was carried out. Blood samples were coEected at the time inter¬ vals mentioned above and the concentration of IP3 was determined in each sample. By calculating the area under the curve (AUC) from a graph where the concentration versus time is shown and comparing the obtained value with a simEiar calculation from the data after intravenous injection of the substance the bioavaEabEity for this specific formulation is obtained. StiE another five pigs were given the penta-sodium salt of IP3 oraEy. Blood samples were coEected at the same time intervals as above and the concen¬ tration of IP3 was determined. FoEowing a simEar procedure the AUC was de¬ termined. The foEowing concentrations of IP3 were obtained after intravenous injection of the sodium salt, after oral administration of the N(3-dodecanoyl- oxy)propyltrimethyl ammonium salt and after oral administration of the so¬ dium salt respectively. time (hrs) 0 0.25 0.5 1.0 2.0 4.0 6.0 8.0 24.0 Normalized AUC (%) 100 46 The bioavaEabEity of the oral formiEation consisting of the quarternary am¬ monium salt of IP3 was 46 %. Example 3 The bioavaEabEity of N-(hexyloxycarbonyl)methyl trimethyl ammonium inosi¬ tol trisphosphate after oral administration was determined with a method similar to the description in Example 2. Five pigs were given an intravenous injection of the penta-sodium salt of IP3 whEe another five animals were given a formulation consisting of the quartemary ammonium salt of IP3 as an in- traduodenal dosing. StiE another group of five pigs were given the penta- sodium. salt of IP3 oraEy. Blood samples were coEected and the concentration of IP3 were determined. The foEowing concentrations of IP3 were obtained after intravenous injection of the sodium salt after oral administration of the N-(hexyloxycarbonyl) methyltrimethyl ammonium salt and after oral administration of the sodium salt respectively. The bioavaEabEity of the oral formulation consisting of the quarternary am¬ monium salt of IP3 was 75%. Irritancy test showed no toxic effects on the in¬ testinal barriers. Example 4 The bioavaEabEity of a formulation consisting of dodecyldimethyl amine and D-myo-inositol-1.2.6-trisphosphate (IP3) after oral administration was deter¬ mined with a method simEar to the description in Example 2. Five pigs were given an intravenous injection of the penta-sodium salt of IP3 whEe another five animals were given a formulation consisting of dodecyldimethyl amine and D?3 as an intraduodenal dosing. StiE another group of five pigs were given the penta-sodiu salt of IP3 oraEy. Blood samples were coEected and the concentration of IP3 were determined. The foEowing concentrations of IP3 were obtained after intravenous injection of the sodium salt, after oral administration of the formulation consisting of dodecyldimethyl amine and IP3 and after oral administration of the sodium salt of IP3 respectively. time intravenous (hrs) injection, 0 0 0.25 71.0 0.5 47.5 1.0 24.9 2.0 9.3 4.0 3.2 6.0 1.1 8.0 0.4 24.0 0.2 Normalized AUC (%) 100 23 The bioavaEabEity of the oral formulation consisting of the amine composition was 23 %.

Claims: CLAIMS 1. An inositol phosphate containing pharmaceutical composition which com¬ prises a nitrogen-containing compound for improvement of the bioavaEabiEty of the inositol phosphate in mammals including man at non-parenteral ad¬ ministration. 2. A composition according to claim 1. wherein the nitrogen-containing com¬ pound is a quarternary ammonium compound. 3. A composition according to claim 2, wherein the inositol phosphate and the nitrogen-containing compound are forming ion-pair structures. 4. A composition according to claim 2, wherein the quarternary amine has. the formula + N(RιR2 R 3) R 5 wherein Rj, R2 and/or R3 are i) hydrogen; E) a straight or branched alkyl with 1 to 24 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, hepta- decyl, octadecyl, eicosyl and/or docosyl; Ei) cycloalkyl with 3 to 16 carbon atoms such as cyclopropyl, cyclopentyl and/or cyclohexyl; iv) alkenyl, with 2 to 24 carbon atoms such as vinyl, aEyl, propenyl, oc- tadienyl, octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, oc- tadecenyl. octadecadienyl. nonadecenyl, octadecatrienyl and/ or arachidonyl; v) cycloalkenyl with 5 to 16 carbon atoms such as cyclopentenyl, cyclo- pentadienyl, cyclohexenyl and/or cyclohexadienyl; vi) aryl with 6 to 24 carbon atoms such as phenyl and/or biphenyl; vE) araLkyl, alkaryl, aralkenyl, alkenaiyl wherein alkyl, aryl and alkanyl are a previously defined. The above groups (E) to (vE) are unsubstituted or substituted with hydroxy; oxo; alkoxy; aryloxy; carboxy; esterified carboxy; amino; substituted amino; formyl; acyl aryloxy; or acylamine and wherein R5 is i) -(CH2) n OCORg wherein n > 2 and wherein Rg is (l)a straight or branched alkyl with 1 to 24 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, eicosyl and/ or docosyl; (2) alkenyl with 2 to 24 carbon atoms such as vinyl, aEyl, propenyl, octadienyl, octenyl, decenyl, dodecenyl. tetradecenyl, hexadecenyl, octadecenyl, octadecadienyl, nonadecenyl, octadecatrienyl and/or arachidonyl; (3)-CH 2 CH(CH 3 )OCOR 1 . -CH(CH 3 )CH 2 OCOR 1 . -CH2CH(OCORι)CH 2 OCOR 1 , -CH(CH 2 OCOR 1 ) 2 . -CH 2 CH(OH)CH 2 OCOR 1 , -CH 2 CH(CH2OH)OCOR 1 , -CH(CH2θH)CH2θCOR! or -CHtCHsJCOORx wherein R * L is as defined above. E) ~(CH~) n ORg wherein n and Rg are as defined above, iu) -(C(Ry)2)n COORg wherein n > 1 and wherein Rg is as defined above and wherein Ry is (l)hydrogen; (2)methyl. ethyl, propyl, butyl and/or pentyl; Iv) -C(Ry)2 OCORg wherein Rg and Ry are as defined above. 5. A composition according to claim 4 wherein Rχ f R2 and/or R3 are i) hydrogen; E) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/or octyl; and wherein R5 is -(CH2) OCORg wherein Rg is selected from hexyl, heptyl, octyl, nonyl, * decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/ or hexadecyl. 6. A composition according to claim 4 wherein Rχ < R2 and/or R3 are i) hydrogen; E) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/or octyl; and wherein R5 is -(CH2)2 01 6 wherein Rg is selected from the group of hexyl, heptyl, octyl. nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/ or hexadecyl. 7. A composition according to claim 4 wherein Rj, R2 and/or R3 are i) hydrogen; E) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/ or octyl; and wherein R5 is -C(Ry)2 COORg wherein Rg is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/or hexadecyl and wherein Ry is i) hydrogen; ii) a straight or branched alkyl selected from the group of methyl, ethyl, propyl and/ or butyl. 8. A composition according to claim 4 wherein Rj, R2 and/or R3 are i) hydrogen; E) a straight or branched alkyl selected from the group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and/ or octyl: and wherein R5 is -C(Ry)2OCORg wherein Rg is selected from the group of hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl and/ or hexadecyl and wherein Ry is i) hydrogen; E) a straight or branched alkyl selected from the group of methyl, ethyl, propyl and/ or butyl. 9. A composition according to claim 1, wherein the nitrogen-containing com¬ pound is a tertiary amine. 10. A composition to any one of claims 1-9, wherein the inositol phosphate is at least one specific isomer of inositoltrisphospahte (IP3). 11. A compsotion according to claim 10, wherein the isomer of IP3 is D-myo- inositol- 1 ,2, 6-trisphosphate. 12. A composition according to claim 10 or 11, wherein the IP3 is present in salt form. 13. A composition according to any one of claims 1-12 in capsule, tablet or granulated form. 14. A composition according to any one of claims 1- 12 in a combined dosage form. 15. The use of at least one nitrogen-containing compound for the preparing of an inositol phosphate containing medicament with improved bioavaEabiEty of inositol phosphate in mammals including man at non-parenteral administra¬ tion. 16. The use according to claim 15, wherein the nitrogen-containing com¬ pound is a quarternary ammonum compound. 17. The use according to claim 15 or 16, wherein the inositol phosphate is an isomer of inositol trisphosphate. 18. The use according to claim 17, wherein the isomer of inositol tris¬ phosphate is D-myo-inositol-l,2,6-trisphosphate. 19. The use according to any one of claims 15-18, wherein the nitrogen- containing compound forms an ion pair structure with the inositol phosphate.

Inventors: PERSSON LARS, PERSSON, LARS
Applicants: PERSTORP AB
Application year: 1993
Main classification: A61K31
IPC codes: A61K31