WO2012066347A1

WO2012066347A1 - Oil based formulations

Info

Publication number: WO2012066347A1
Application number: PCT/GB2011/052262
Authority: WO
Inventors: Richard Franklin; Bernard Golding
Original assignee: Shire, Llc
Priority date: 2010-11-18
Filing date: 2011-11-18
Publication date: 2012-05-24
Also published as: GB201019525D0

Abstract

The present invention relates to the use of oil based delivery vehicles to prevent undesirable premature hydrolysis of phenolic amino benzoic acid carbamate prodrugs, while resident in the gut lumen. Preclusion of water and hydrolytic enzymes prior to prodrug absorption ensures that such compounds can be fully absorbed intact without undergoing unintended premature hydrolysis in the gastrointestinal tract so maximizing the benefit of improved systemic availability afforded by the prodrug. Furthermore judicious selection of oil and prodrug salt form can result in a sustained release plasma PK profile. The avoidance of premature degradation and release of active drug into the gut lumen minimizes any potential for a direct adverse interaction within the gut lumen.

Description

OIL-BASED FORMULATIONS

FIELD OF THE INVENTION

[01] The present invention relates to the use of oil based delivery vehicles to prevent undesirable premature hydrolysis of phenolic amino benzoic acid carbamate prodrugs, while resident in the gut lumen. Preclusion of water and hydrolytic enzymes prior to prodrug absorption ensures that such compounds can be fully absorbed intact without undergoing unintended premature hydrolysis in the gastrointestinal tract so maximizing the benefit of improved systemic availability afforded by the prodrug. Furthermore judicious selection of oil and prodrug salt form can result in a sustained release plasma PK profile. The avoidance of premature degradation and release of active drug into the gut lumen minimizes any potential for a direct adverse interaction within the gut lumen.

BACKGROUND OF THE INVENTION

[02] In many instances prodrugs - biologically reversible, derivatised drugs - offer the potential for real advantage over the parent drug in a number of ways. Prodrugs may improve the systemic delivery of the parent drug which might otherwise be compromised by incomplete absorption from the gut. For example oral absorption of the important antiviral agent acyclovir is normally very poor (15-30%) due to its poor solubility but the use of the valine ester prodrug valacyclovir ensures much improved, 2-5-fold, absorption due to it facilitated active transport (Weller S et al (1993) Clin Pharmacol Ther 54 595-605). Despite the benefits this offers some unintentional premature chemical and biological hydrolysis of valacyclovir (up to 25%) may occur in the gut lumen before the drug has been absorbed. This will inevitably reduce the amount of drug available for assisted absorption (Granero GE & Amidon GL (2006) Internat. J Pharmaceut. 317 14-18).

[03] Another potential benefit to the use of prodrugs is avoidance of initial high first pass metabolism in the gut wall or liver. For example acetyl salicylate or anthranilic acid esters has been shown to be of value in improving the oral bioavailability of drugs such as naltrexone (Hussain MA & Shefter E (1988) Pharm Res. 5, 1 13-5) and oestradiol (Hussain MA et al, (1988) Pharm Res. 5, 44-47). However, once again, this approach is susceptible to unwanted premature ester hydrolysis in the gut lumen reducing the amount of "protected drug" available for absorption and capable of delivering active to the systemic circulation. More recently para amino benzoic acid carbamate conjugates of phenolic opioids such as meptazinol, tapentadol and buprenorphine have been shown to substantially increase the oral bioavailability of the parent active opioid (U.S. Provisional Patent Application Serial No. 61/292,362). However by their nature such compounds may be intrinsically susceptible to chemical hydrolysis. [04] Pharmacologically inactivated prodrugs have the potential to avoid or reduce Gl side-effects normally elicited by direct action of the active drug on the gut mucosa or within the gut lumen. For example the inactivated benzoyl ester prodrug of galantamine Memogain® is claimed to reduce the incidence of locally mediated emesis normally associated with the parent drug (Maelicke A et al (2010) J Mol Neurosci 40, 135-137). However premature gut luminal hydrolysis of this ester could make available some of the active drug potentially capable of eliciting an unwanted direct action on the gut.

[05] Prodrugs are, by definition, biologically and/or chemical unstable but as mentioned above this should ideally not occur in the gut lumen as this will reduce the amount of protected or absorbable prodrug available and may result in active drug adversely affecting the gut. Generation of the active drug should only occur after absorption, in the liver or systemic circulation and not in the gut. If chemical hydrolysis plays a predominant role in the release of the active, as for example in the cleavage of the ester prodrug of valacyclovir, this has the potential to significantly contribute to premature gut luminal hydrolysis.

[06] Furthermore if chemically mediated hydrolysis is a major drug release mechanism the shelf-life of such a formulated prodrug product may be adversely impacted by any tendency to undergo premature chemical hydrolysis due to atmospheric moisture.

[07] Amino benzoic acid carbamates (e.g. para-amino benzoic acid carbamates) may represent a useful class of non toxic prodrugging moieties, but which are very susceptible to such premature chemical hydrolysis. This propensity to chemical (pH dependent) hydrolysis is due to the labilising influence of the closeness of the aromatic ring to the carbamate nitrogen. If this problem could be overcome, the full potential of this and other chemically and/or biologically labile prodrugging moieties could be exploited.

[08] There thus remains an important need to devise a means of avoiding the unwanted premature hydrolysis of particularly chemically and enzymically labile prodrugs such as phenolic carbamates using amino benzoic acid as the prodrugging entity.

SUMMARY OF THE INVENTION

[09] The present invention affords a means of avoiding premature gut luminal degradation via chemical or enzymic cleavage to the active drug molecule and any unwanted consequences e.g. loss of absorbable intact prodrug and/or adverse Gl events.

[010] According to a first aspect, the present invention provides a pharmaceutical composition comprising: (a) an amino benzoic acid carbamate prodrug of an approved therapeutically active compound including one or more phenolic groups, its pharmaceutically acceptable salts, pharmaceutically acceptable esters or pharmaceutically acceptable salts of esters; and (b) a pharmaceutically acceptable oil-based delivery vehicle. [011] According to a second aspect, the present invention provides a pharmaceutical composition of the first aspect of the use as a medicament.

[012] According to a third aspect, the present invention provides a use of an oil-based delivery vehicle to prevent hydrolysis of an amino benzoic acid prodrug of an approved therapeutically active compound including one or more phenolic groups.

[013] According to a fourth aspect, the present invention provides a use of an oil-based delivery vehicle to preserve the chemical integrity of amino benzoic acid prodrugs of phenolic pharmaceuticals to enable their active transport/absorption from the Gl tract.

DESCRIPTION OF FIGURES

[014] The invention is illustrated by way of the following figures, in which:

[015] Figure 1 illustrates the plasma buprenorphine concentrations versus time after various formulations of buprenorphine PABA carbamate given orally to monkeys.

[016] Figure 2: Plasma meptazinol concentrations versus time after various formulations of meptazinol PABA carbamate given orally to monkeys.

DETAILED DESCRIPTION OF THE INVENTION

[017] Definitions:-

[018] The term "delivery vehicle" refers to a component in which an active compound is dispersed or dissolved. The pharmaceutical compositions of the invention may contain combinations of more than one delivery vehicle. Such delivery vehicles can be oils, including those of petroleum, animal, vegetable or synthetic origin.

[019] The term "oil-based" means that the delivery vehicle is substantially oil. Other components may be present as excipients, but the bulk of the delivery vehicle is oil. The delivery vehicle is thus substantially free of water.

[020] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are generally regarded as safe. In particular, pharmaceutically acceptable delivery vehicles used in the practice of this invention are physiologically tolerable and do not typically produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a patient. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the appropriate governmental agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[021] The term "active compound," unless specifically indicated, is to be understood as referring to the drug portion of a prodrug of the present invention, as described herein. [022] The term "salts" can include acid addition salts or addition salts of free bases. Suitable pharmaceutically acceptable salts (for example, of the carboxyl terminus of a para amino benzoic acid prodrug ) include, but are not limited to, metal salts such as sodium potassium and cesium salts; alkaline earth metal salts such as calcium and magnesium salts; organic amine salts such as triethylamine, guanidine and N-substituted guanidine salts, acetamidine and /v-substituted acetamidine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, and Ν,Ν'-dibenzylethylenediamine salts. Pharmaceutically acceptable salts (of basic nitrogen centers) include, but are not limited to inorganic acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate; organic acid salts such as trifluoroacetate and maleate salts; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphor sulfonate and naphthalenesulfonate; and amino acid salts such as arginate, gluconate, galacturonate, alaninate, asparginate and glutamate salts (see, for example, Berge, ef al. "Pharmaceutical Salts," J. Pharma. Sci. 1977; 66: 1 ).

[023] Hydrophile-Lipophile Balance (HLB) is an empirical expression of the relationship of the hydrophilic ("water-loving") and hydrophobic ("water-hating") groups of an oil. Thus the (HLB) value of any pharmaceutically acceptable oil is a measure of its tendency towards being water or fat miscible. HLB values less than 10 tend to be readily oil soluble while those more than 10 tend to be more water soluble.

[024] As used herein, the term "soft gelatin dosage unit" is intended to encompass any dosage unit and/or form which employs a gelatin or non animal alternative casing. Numerous casing materials have been proposed for soft capsules including gums, carrageenans, hydroxypropylated starches, celluloses, and the like. As used herein, the term "soft gelatin dosage unit" means a dosage form constructed of mammalian gelatin, fish gelatin, gums, guars, carrageenans, modified starches and the like.

[025] The term "elixir" herein refers to is a flavored sweet oily liquid in which the prodrug is dissolved or suspended.

[026] Micron isation is defined as the process by which a material is reduced in size, often to micrometer proportions. Typically micronised pharmaceutical products may have a particle size ranging from 0.1 to 10.0 μιη [027] Compositions of the invention

[028] In an embodiment of the present invention, the amino benzoic acid carbamate prodrug has a structure:

wherein: the term "drug" means a drug having a phenolic group;

R is independently selected at each occurance from the group consisting of: hydroxy, carboxy, acetyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), Ci_₆ alkyl (e.g. methyl, ethyl or propyl), Ci_₆ haloalkyl (e.g. trifluoromethyl), d. 6 alkoxy (e.g. methoxy, ethoxy or propoxy), Ci_₆ haloalkoxy (e.g. trifluoromethoxy), C₃. 6 cycloalkyl (e.g. cyclohexyl), aryl (e.g. phenyl), aryl-Ci_₆ alkyl (e.g. benzyl) or Ci_₆ alkyl aryl;

R' is selected from the group consisting of: H and C-i_₆ alkyl (e.g. methyl, ethyl or propyl); and n is from 0 to 3; or a pharmaceutically acceptable salt thereof.

[029] In an embodiment, n is from 0 to 2. Preferably, n is 0 or 1. [030] In an embodiment, R is -OH.

[031] In an embodiment, R' is selected from the group consisting of: H, Me and Et. Preferably, R' is H.

[032] In an embodiment, -COOR' is para- to the -NH- group. In an embodiment, - COOR' is meta- to the -NH- group.

[033] In an embodiment, the pharmaceutical composition is in unit dosage form.

[034] The amount of the oil in the oil based delivery system is sufficient to dissolve or at least partially dissolve the prodrug.

[035] In an embodiment, the pharmaceutical composition further comprises pharmaceutically suitable anti-oxidants/stabilisers and/or surfactants and/or preservatives. The purpose of the surfactant is to facilitate dissolution of the prodrug salt in the delivery vehicle.

[036] In an embodiment, the pharmaceutical composition further comprises a pharmaceutically ingestible containment system or other delivery system for oily formulations.

[037] In an embodiment, the phenolic drug is a phenolic opioid drug. Examples of phenolic opioid drugs include: buprenorphine, butorphanol, dezocine, hydromorphone, ketobemidone, levorphanol, meptazinol, morphine, nalbuphine, nalorphine, naloxone, oxymorphone, pentazocine and tapentadol.

[038] In an alternate embodiment, the phenolic drug is a non-opioid phenolic drug. Examples of non-opioid phenolic drugs include: apomorphine, curcumin, fenretinide, dextrorphan, L-dopa, dronabinol (Δ9 tetrahydrocannibinol), nabilone, oestriol, oestradiol, oestrone, raloxifene, rotigotine, and resveratrol.

[039] In some instances there may be more than one possible position of derivatisation in a drug molecule to which the prodrugging entity may be attached. In other words, the drug may contain more than phenolic hydroxyl group. It is a preferred embodiment, that when the drug molecule includes more than one possible position of derivatisation, the prodrug of the invention has only a single amino benzoic acid carbamate group conjugated to the drug molecule. The present invention embraces any possible position of substitution by the amino benzoic acid carbamate group on the drug molecule. Preferably, the position of prodrugging conjugation with the amino benzoic acid is that normally susceptible to first pass metabolism and/or nearest the pharmacophoric region (when that is known). In a further embodiment it is also envisaged that additional prodrugging moieties may be present at other phenolic positions within the drug molecule.

[040] In an embodiment, the amino benzoic acid portion of the carbamate prodrug of the present invention is selected from the group comprising: para-amino benzoic acid, 4-amino acid salicylic acid and 5-amino salicylic acid.

[041] The pharmaceutically acceptable salt of these drugs may be selected from a wide range embracing differing hydro/lipophilicities and would include but is not restricted hydrophilic salts such as hydrochloride, hydrobromide, maleate, and trifluoroacetate and lipophilic salts such as camphor sulphonate, naphthalene sulphonate, and toluene sulphonate.

[042] The pharmaceutically acceptable oils of the oil-based delivery vehicle can be selected from a wide spectrum oils of differing hydro/lipophilicities as defined by their hydrophilic - lipophilic balance (HLB) values. In an embodiment, the pharmaceutically acceptable oil is selected from the group comprising: almond oil, canola oil, castor oil, cotton seed oil, corn oil, (fractionated) coconut oil, olive oil, peanut oil (arachis oil), sesame seed oil, sunflower oil, medium chain mono and diglycerides, hydrogenated vegetable oil, medium chain triglycerides, mineral oil, a tocopherol, capric or caprylic triglycerides and glycerol stearate. In an alternate embodiment, the pharmaceutically acceptable oil is Gelucire 44/14® (Gelucire 44/14® is available from the company Gattefosse; is a lauroyi macrogol-32 glyceride EP / lauroyi polyoxyl-32 glyceride NF; is a non-ionic water dispersible surfactant composed of well-characterized PEG-esters, a small glyceride fraction and free PEG). In a preferred embodiment, the pharmaceutically acceptable oil is selected from the group comprising: cotton seed oil, peanut oil, Capmul®, Miglyol® 810 or 812 and combinations thereof. A fuller list of pharmaceutically acceptable oils can be found in the "Handbook of Pharmaceuticals Excipients" edited by Rowe RC, Sheskey PJ, and Weller PJ, Pharmaceutical Press 2003.

[043] In an embodiment, the pharmaceutically acceptable anti-oxidant is selected from the group comprising: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), monothioglycerol, ethylene diamine tetra acetic acid (EDTA), thiourea and tocopherol.

[044] In an embodiment, the surfactant is selected from the group comprising: lecithin, various phospholipids, polysorbate (e.g. Tween® such as Tween® 20, 40 or 80), polyethylene castor oils (e.g. Cremphor® EL) and polyethylene glycols (e.g. PEG 400). In an alternate embodiment, the surfactant includes a sorbitan fatty acid ester (SPAN) which is a non-ionic surfactant. SPANs offer greater viscosity than surfactants such as Tween and thereby may provide better suspending properties.

[045] In an embodiment, the surfactant is included in the pharmaceutical composition at a range of from about 0.1 % to about 15% w/w, preferably from about 5% to about 15% w/w. The surfactant minimises the risk of particle aggregation in the formulation suspension.

[046] In a particularly preferred embodiment, the pharmaceutically acceptable oil of the pharmaceutical composition is selected from the group consisting of: Miglyol® 810, Miglyol® 812 and Gelucire 44/14®; the pharmaceutical composition comprises a surfactant selected from the group consisting of: Tween® 20, 40 and 80; and the surfactant included in the pharmaceutical composition is in the range of from about 5% to about 15% w/w.

[047] In an embodiment, the pharmaceutical composition is contained in a soft or hard gelatin capsule. In an embodiment, the pharmaceutical composition is contained in a soft gelatin capsule. Preferably the gelatin capsule is a size zero soft gelatin capsule. Non gelatin alternatives include agar-agar (a seaweed), carrageenan, pectin, and konjak. In an alternate embodiment, the pharmaceutical composition is contained in a tablet with a porous matrix. Examples of porous matrices include Neusilin® (a magnesium aluminometasilicate), Fujicalin® (a dibasic anhydrous calcium phosphate) or porous hydroxyapatite. The porous matrix facilitates the incorporation of oils. In an alternate embodiment, the pharmaceutical composition of the present invention may simply be administered as a measured volume elixir.

[048] In one embodiment the prodrugs of the present inventions are meptazinol amino benzoic acid carbamate, buprenorphine amino benzoic acid carbamate, butorphanol amino benzoic acid carbamate, dezocine amino benzoic acid carbamate, hydromorphone amino benzoic acid carbamate, ketobemidone amino benzoic acid carbamate, levorphanol amino benzoic acid carbamate, morphine amino benzoic acid carbamate, nalbuphine amino benzoic acid carbamate, naloxone amino benzoic acid carbamate, nalorphine amino benzoic acid carbamate, oxymorphone amino benzoic acid carbamate, pentazocine amino benzoic acid carbamate, tapentadol amino benzoic acid carbamate.

[049] Non-opioid prodrugs include apomorphine amino benzoic acid carbamate (mono or di), curcumin amino benzoic acid carbamate, L-dopa (mono or di) amino benzoic acid carbamate, dronabinol amino benzoic acid carbamate, dextrorphan amino benzoic acid carbamate, fenretinide amino benzoic acid carbamate, oestradiol amino benzoic acid carbamate, oestriol amino benzoic acid carbamate, oestrone amino benzoic acid carbamate, nabilone amino benzoic acid carbamate, raloxifene amino benzoic acid carbamate, rotigotine amino benzoic acid carbamate, or resveratrol amino benzoic acid carbamate.

[050] The prodrugs are presented as their free base/acids, hydrochloride, hydrobromide, maleate, trifluoroacetate, camphor sulphonate, naphthalene sulphonate, toluene sulphonate or other appropriate salts.

[051] In one embodiment of the invention, the formulation comprises 100% refined cotton seed oil containing dissolved or suspended prodrug in a suitable salt or free base/acid form. The specification for refined cotton seed oil can be found in the US National Formulary monograph and typically contains; C16:0 fatty acid, 17-29%, C18:1 fatty acid 13-44% and C18 :2 fatty acid, 40-63% as well as minor amount of C14:0,C16: 1 , C18:0, C18:3.

[052] In yet a further embodiment of the invention the formulation comprises 100% refined peanut oil (approximate HLB value, 6) containing dissolved or suspended prodrug in a suitable salt or free base/acid form. The specification for refined peanut oil can be found in the US National Formulary monograph and typically contains the following fatty acids; C16:0 6- 15.5%, C18: 1 36-72%, C18:2 13-45% with minor amount of C14:0, C16:1 , C18:3, C20:0, C20: 1 , C20:4, C22:0 and C24:0.

[053] In yet a further embodiment of the invention the formulation comprises 100% Capmul® MCMC-8, EP containing dissolved or suspended prodrug in a suitable salt or free base/acid form. The specification for Capmul® MCMC-8, EP can be found in the European Pharmacopeia Monograph for Glycerol Monocaprylate, Type 1. It is a mono-, diglyceride of medium chain fatty acids (mainly caprylic). It is a mixture of monoacylglycerols mainly mono- O-octanoylglycerol containing variable quantities of di-and triacylglycerols, obtained by direct esterification of glycerol with caprylic (octanoic) acid

[054] In another embodiment of the invention the formulation comprises 100% Miglyol® 810 or 812 (approximate HLB value 1 1 ) containing dissolved or suspended prodrug in a suitable salt or free base/acid form. Miglyol® 810 or 812 contains caprylic and capric triglyceride as defined by the USP National Formulary 22 or European Pharmacopeia for medium-chain triglycerides or the British Pharmacopeia for fractionated coconut oil. Other Miglyols are envisaged and include 818, 829 and 840 neutral oils.

[055] In yet a further embodiment of the invention, various mixtures of all or some of the aforementioned oils are envisaged in order to give an optimal HLB value for delivery of the prodrug in question.

[056] Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.) as well as ascorbic acid.

[057] In another embodiment, pharmaceutical composition is an elixir including a sweetened flavoured oily solution or suspension of the prodrug. Preferred masking flavours include cherry, blueberry, raspberry, backcurrant or strawberry. The use of pharmaceutically acceptable odorants may be required for the elixir compositions and would include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions. Suitable examples of pharmaceutically acceptable sweeteners include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.

[058] The prodrug suspension may be one of micronised material of suitable particle size.

[059] Advantages of the compositions of the invention

[060] Without wishing to be bound to any particular theory, it is believed that the use of selected oil formulations of chemically or enzymically labile prodrug for oral administration reduces the potential for premature hydrolysis of the said prodrug. Such formulations deny access to water or hydrolytic enzymes which would otherwise bring about hydrolysis of the prodrug. Preserving the chemical integrity of the prodrug is essential in order to exploit the active transporter in the gut wall believed responsible for absorption of these prodrugs. Premature gut luminal hydrolysis of a prodrug back to the parent drug would prevent access to this absorption mechanism which has strict structural requirements usually present only in the prodrug. For example utilisation of the PepT1 transporter requires the presence of a peptide bond while use of the monocarboxylic acid transporter (MCT) or ceftibuten/fluoroscein transporter requires an aryl carboxylic acid residue. Neither of these features is usually present in the parent structures of the preferred drugs under consideration in this present invention. The features are certainly not both present in the parent structures of the preferred drugs under consideration. Utilisation of active transport mechanisms enables improved absorption of these prodrugs which could not otherwise be affected by the more usual simple diffusional process. The use of these prodrugs affords transient protection against gut wall and hepatic first pass metabolism, to which the drug itself is normally exposed. The use of a carefully selected oil based formulation ensures minimisation of the aforementioned premature gut luminal hydrolysis and so preserves the chemical integrity of these prodrugs. The resultant more consistent absorption of protected drug will ensure improved patient treatment.

[061] Again without wishing to be bound by any particular theory it is believed that the hydrolysis of the phenolic PABA carbamates of the invention is pH ( H+ ion) dependent as shown in the scheme below:-

Postulated, so-called "E2b" mechanism for the pH mediated chemical hydrolysis of phenolic PABA carbamates of the invention

[062] Precluding access to H+ and OH- to the prodrugs will limit their ability to undergo such hydrolysis. Furthermore precluding access to water-soluble enzyme hydrolases such as carboxylpeptidase, which might normally be expected to effect biological cleavage of these carbamate prodrugs, would also be denied.

[063] Furthermore it is an object of this invention to enable improved formulation stability and hence product shelf life when this may be compromised by premature hydrolysis of the prodrug due contact with moisture. The formulations of this invention would preclude access of water to these pH/water labile phenolic PABA carbamate prodrugs.

[064] It is a further benefit of the invention that to enable protracted absorption from the Gl tract by advantageously exploiting the partitioning behaviour of the prodrug salt from the particular oil formulation into the adjacent intestinal epithelium. This can facilitate protracted /sustained absorption and so provide an enhanced plasma drug concentration-time profile so reducing dosing frequency and thereby improving patient compliance and treatment. Selection of appropriate salt forms of the prodrugs of the present invention can be facilitated by the determination of their partitioning behaviour between octanol and water at pH 7.4 allowing estimation of the so-called logP values. The higher the logP, the greater the propensity to remain in the oil-based delivery vehicle and the slower and more protracted the in vivo absorption process is likely to be.

[065] A further benefit of this invention is the avoidance of premature release of the active drug in the gut lumen and unwanted interactions with gut opioid or other receptors that may normally bring about unwanted effects e.g. hypomotility and constipation. Alternatively where the phenolic drug is a cytotoxic agent avoidance of the presence of active drug in the gut lumen would serve to limit the nausea, vomiting and diarrhoea associated with the direct cytotoxic actions on the gut epithelial cells.

[066] Uses and Methods of the Invention

[067] One embodiment of the present invention is a method of treating a disorder in a subject in need thereof. The method comprises orally administering a therapeutically effective amount of a selected prodrug formulation of the present invention to the subject. The disorder may be one treatable with the drug such as pain of varying aetiology (dronabinol and nabilone). Alternatively the condition may be anyone of a number of diseases such as Parkinsonism (apomophine, L-dopa, rotigotine), osteoporosis and breast cancer (raloxifene) menopausal symptoms (oestradiol, oestrone, oestriol), cancers of a wide diversity (lymphoid, myeloid, multiple myeloma, breast, stomach, prostate, liver, pancreas, colon and thyroid (resveratrol and curcumin) treatable with the formulated prodrugs of the invention.

[068] The prodrug formulations encompassed by the present invention may be administered in conjunction with other therapies and/or in combination with other complementary active agents. In such combination therapies, the prodrug formulations encompassed by the present invention may be administered prior to, concurrent with, or subsequent to the other therapy and/or active agent.

[069] In one embodiment, the present invention is directed to a method for minimizing the unwanted premature chemical and/or enzymic instability of the prodrug in the gut lumen - - and effective loss of absorbable prodrug - normally seen after administration of the unformulated prodrug. The method comprises orally administering a prodrug formulation to a subject in need thereof, wherein the prodrug formulation is comprised a judiciously selected salt form dissolved or suspended in carefully selected oil or oil combination. Where the prodrug is in suspension the particle size is optimal for the desired rate of dissolution and absorption and may, where necessary, be the result of micronization.

[070] In yet a further embodiment, the present invention is directed to a method for minimising the potential for any direct adverse interactions of the active drug within the gut lumen compared to those seen with use of the unformulated prodrug. The method comprises preparing a prodrug formulation of a judiciously selected salt form dissolved or suspended in a carefully selected oil or oil emulsion. Where the prodrug is in suspension, the particle size is optimal for the desired rate of dissolution and absorption and may, where necessary, be the result of micronization.

[071] In yet a further embodiment, the present invention is directed to a method for sustaining the delivery of the prodrug compared to that seen with use of the unformulated prodrug. The method comprises preparing a prodrug formulation comprising a judiciously selected salt form dissolved or suspended in a carefully selected oil. Where the prodrug is in suspension the particle size is optimal for the desired rate of dissolution and absorption and may, where necessary, be the result of micronization. The sustainment of plasma active drug concentrations should be at least 20% longer than when the unformulated prodrug administered.

[072] Pharmaceutical formulations of the Invention

[073] While it is possible that, for use in the methods of the invention, the compositions of the present invention may be administered as simple elixirs, it is preferable to present the composition appropriately encapsulated in hard or soft gelatin or non-gelatin capsules or incorporated into suitable tablets or caplets. Capsules may be of varying sizes 00-4 and may contain volumes up to ~1 ml (size 00). Tablets may be of whatever size is deemed likely to be acceptable to the patient.

[074] Capsules may be hard or soft gelatin. As used herein, the term "soft gelatin dosage unit" means a dosage form constructed of mammalian gelatin, fish gelatin, gums, guars, carrageenans, or modified (hydroxypropylated) starches. Hard gelatin capsules may be two piece, sealed capsules and, as with soft gelatin, be of any colour (or colourless ) or shape. Examples of suitable pharmaceutically acceptable dyes include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.

[075] Alternatively the pharmaceutical compositions of the invention may be incorporated into tablets comprising porous matrices. For example the use of porous matrices such as Neusilin® (a magnesium aluminometasilicate), Fujicalin® (a dibasic anhydrous calcium phosphate (DCHA) or porous hydroxyapatite facilitate the incorporation of oils. The use of these materials enables development of free flowing powders of oily compositions that have excellent tablettability.

[076] The formulations of the present invention can be administered from one to six times daily, depending on the dosage form and dosage.

[077] The formulations of the present invention may used in human or veterinary medicine. The invention therefore includes pharmaceutical formulations of the inventions adapted for use in human or veterinary medicine.

[078] The pharmaceutical compositions of the invention may contain from 0.01 to 99% weight per volume of the prodrugs encompassed by the present invention.

[079] Dosages

[080] Appropriate patients to be treated according to the methods of the invention include any human or animal in need of such treatment. Methods for the diagnosis and clinical evaluation of the disease condition including its severity in an animal or human will be well known in the art. Thus, it is within the skill of the ordinary practitioner in the art (e.g., a medical doctor or veterinarian) to determine if a patient is in need of treatment. The patient is preferably a mammal, more preferably a human, but can be any subject or animal, including a laboratory animal in the context of a clinical trial, screening, or activity experiment employing an animal model. Thus, as can be readily appreciated by one of ordinary skill in the art, the methods and compositions of the present invention are particularly suited to administration to any animal or subject, particularly a mammal, and including, but not limited to, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc.

[081] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

[082] Depending on the severity of the condition to be treated, a suitable therapeutically effective and safe dosage, as may readily be determined within the skill of the art, can be administered to subjects. The daily dosage level of the prodrug formulation may be administered in single or multiple doses. The duration of treatment may be determined by one of ordinary skill in the art, and should reflect the nature of the condition and/or the rate and degree of therapeutic response to the treatment. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. [083] The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the particular compounds in the mutual prodrug employed, the age, body weight, general health, sex, diet, the severity of the particular condition, and the individual undergoing therapy

[084] In the methods of treatment, the prodrug formulations encompassed by the present invention may be administered in conjunction with other therapies and/or in combination with other active agents. For example, the prodrug formulation encompassed by the present invention may be administered to a patient in combination with other active agents used to treat that condition. An active agent to be administered in combination with the prodrug formulation is encompassed by the present invention. In such combination therapies, the prodrug formulation encompassed by the present invention may be administered prior to, concurrent with, or subsequent to the other therapy and/or active agent.

[085] Where the prodrug formulations encompassed by the present invention are administered in conjunction with another active agent, the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the prodrug formulation encompassed by the present invention or the second active agent may be administered first. For example, in the case of a combination therapy with another active agent, the prodrug formulation encompassed by the present invention may be administered in a sequential manner in a regimen that will provide beneficial effects of the drug combination.

[086] When the prodrug formulations of the present invention are used in combination with another agent active in the methods for treating that condition, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those of ordinary skill in the art.

EXAMPLES

[087] Example 1 - Assessment of chemical/biological stability of buprenorphine PABA carbamate in simulated gastric and intestinal juice

To determine the potential gut luminal stability of buprenorphine PABA carbamate the prodrug was incubated with the classical USP SGF (simulated gastric fluid), and USP SIF (simulated intestinal fluid)

Additionally the stability of buprenorphine PABA carbamate was investigated in what is now considered a more realistic simulated intestinal fluid containing sodium taurocholate and lecithin described as "FaSSIF" (fasted state simulated intestinal fluid) or "FeSSIF" (fed state simulated intestinal fluid).

Method - Prodrug stability was initially determined in USP SGF & USP SIF. Prodrug ( 20ug/ml_) was incubated in USP SGF comprising NaCI 34mM, HCI ~70nM, pepsin 0.32% (overall pH1 .1 ) for 1 h at 37C or USP SIF composed of monobasic potassium phosphate 0.05M, sodium hydroxide 0.15M and 10% w/v pancreatin ( adjusted to pH 6.8) for 2h at 37°C. At the end of this period remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method.

Subsequently the stability of the buprenorphine prodrug was assessed by incubation for 2h at 37°C in the more, in vivo, representative FaSSIF cocktail comprising sodium taurocholate 3mM, lecithin 0.75mM, NaOH 8.7mM, NaH₂P0₄. H₂0 28.7mM, NaCI 106mM, pancreatin 1 % (overall pH 6.5). After acidifying the incubation to stop any reaction the amount of prodrug remaining and drug generated were determined using a qualified LC-MS/MS method.

The corresponding FeSSIF cocktail, was used in comparable manner, and comprised sodium taurocholate 15mM, lecithin 3.75mM, NaOH 101 mM, acetic acid 144mM, and NaCI 202mM (overall pH 5.0). Pancreatin was again added at 1 %. Again remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method.

Results - The prodrug appeared completely stable in simulated gastric juice. However the results in simulated intestinal juice, presented in Table 1 , indicate a marked difference in the apparent stability between the classical SIF and the more recently introduced FaSSIF/FeSSIF.

[088] In the classical USP SIF (used here at pH 6.5) buprenorphine PABA carbamate appeared very unstable with -65% having degraded in the 2h incubation period. By contrast - and surprisingly - the stability of buprenorphine PABA carbamate in FaSSIF was very much more stable being only marginally(<5%) degraded after 2h. It was speculated that this may have been due to the presence of the phospholipid, lecithin, in which the prodrug may have preferentially dissolved and been largely protected from aqueous or enzymic hydrolysis seen in USP SIF.

[089] Example 2 - Comparative effect of various oil formulations of buprenorphine PABA carbamate on the observed pharmacokinetics of resultant buprenorphine in primates

[090] Methods One group of five male Cynomolgus monkeys were orally dosed in a crossover study design with buprenorphine PABA carbamate HCI (0.2mg buprenorphine equivs/kg) in aqueous suspension in hydroxypropyl methyl cellulose (HPMC) or in solutions in cotton seed oil, peanut oil, Capmul® MCM, or Migyol® 812 using a vehicle volume of 2ml_/kg. Femoral vein blood samples were subsequently collected into tubes containing 6.0mg/ml_ NaF, 1.75mg/ml_ K₂EDTA, 10ul 1 M citrate buffer pH 4.3 and 20mM 1 ,4 saccharolactone as prodrug stabilisers. Separated plasma samples were subjected to bioanalysis for both the prodrug and buprenorphine itself using a qualified LC/MS-MS bioanalytical method. Subsequent pharmacokinetic analysis was then undertaken using Win NonLin to generate the relevant PK parameters including AUC and T _/2. [091] Results. These are shown in Tables 2 and Figure 1

[092] While the absolute overall bioavailability of buprenorphine was somewhat lower with three of the oil formulations, the use of Miglyol® 812 appeared to double the systemic availability of buprenorphine possibly due to greater preservation of the stability of the prodrug. Furthermore the sustainment of plasma drug concentrations was considerably greater than after giving a simple HPMC suspension. The T50% Cmax, the period for which the concentrations remained at or above 50% of the maxinum level, was increased from 4.7h ± 16.2% to 8.9h ± 3.5%. This again may be a reflection of the greater stability of the prodrug in the oily vehicle allowing absorption to continue for longer.

[093] Example 3 - Assessment of chemical/biological stability of meptazinol PABA carbamate

[094] To determine the potential gut luminal stability of meptazinol PABA carbamate the prodrug was incubated with the classical USP SGF (simulated gastric fluid), and USP SIF (simulated intestinal fluid).

[095] Additionally the stability of meptazinol PABA carbamate was investigated in the more in vivo comparable simulated intestinal fluid containing sodium taurocholate and lecithin -"FaSSIF" (fasted state simulated intestinal fluid) or "FeSSIF" (fed state simulated intestinal fluid).

[096] Method - Prodrug stability was initially determined in USP SGF & USP SIF. Prodrug ( 20ug/ml_) was incubated in USP SGF comprising NaCI 34mM, HCI ~70nM, pepsin 0.32% (overall pH 1.1 ) for 1 h at 37C or USP SIF composed of monobasic potassium phosphate 0.05M, sodium hydroxide 0.15M and 10% w/v pancreatin (adjusted to pH 6.8) for 2h at 37°C. At the end of this period remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method

Subsequently the stability of meptazinol PABA carbamate was assessed by incubation for 2h at 37°C in a more in vivo representative FaSSIF cocktail comprising sodium taurocholate 3mM, lecithin 0.75mM, NaOH 8.7mM, NaH₂P0₄. H₂0 28.7mM, NaCI 106mM, pancreatin 1 % (overall pH 6.5). After acidifying the incubation to stop any reaction the amount of prodrug remaining and drug generated were determined using a qualified LC-MS/MS method.

The corresponding FeSSIF cocktail, was employed similarly, and comprised sodium taurocholate 15mM, lecithin 3.75mM, NaOH 101 mM, acetic acid 144mM, and NaCI 202mM (overall pH 5.0). Pancreatin was present at 1 %. Again remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method.

[097] Results - The results shown in Table 3

[098] These results show that using the classical USP SIF meptazinol PABA carbamate appeared relatively unstable, with -35% having degraded in the 2h incubation period. By contrast the stability of meptazinol PABA carbamate in FaSSIF was rather greater with 24% degraded after 2h. It was speculated that this may have been due of presence of the phospholipid, lecithin, in which the prodrug could have preferentially dissolved and been largely protected from aqueous or enzymic hydrolysis seen in USP. The greater stability seen in FeSSIF probably simply reflected the expected greater chemical stability of the PABA carbamate prodrug at pH5.0

Example 4 - Comparative effect of various oil formulations of meptazinol PABA carbamate on the observed pharmacokinetics of resultant meptazinol in primates

[099] Methods One group of five male Cynomolgus monkeys were orally dosed in a crossover study design with meptazinol PABA carbamate HCI (2.0mg meptazinol equivs/kg) in aqueous suspension in hydroxypropyl methyl cellulose (HPMC) or in solutions in cotton seed oil, peanut oil, Capmul® MCM, or Migyol® 810 using a vehicle volume of 2ml_/kg. Femoral vein blood samples were subsequently collected into tubes containing 6.0mg/ml_ NaF, 1.75mg/ml_ K₂EDTA, 10ul 1 M citrate buffer pH 4.3 and 20mM 1 ,4 saccharolactone as prodrug stabilisers. Separated plasma samples were subjected to bioanalysis for both the prodrug and meptazinol itself using a qualified LC/MS-MS bioanalytical method. Subsequent pharmacokinetic analysis was then undertaken using Win NonLin to generate the relevant PK parameters including AUC and T_1/2.

[0100] Results. These are shown in Tables 3 & Figure 2.

NA no available yet While the use of oil formulations reduced overall systemic exposure, there was a beneficial reduction in the PK variability. For example in the case of Miglyol, although the bioavailability (AUC) was reduced to 60% of that after an HPMC aqueous suspension of the prodrug, the variability around this parameter dropped dramatically from 44% (CoV) to 23%. There was also a reduction in the relative standard deviation round the Cmax which fell from 61 to 35%. There was also a significant prolongation of the T50%Cmax value, the period for which the concentrations remained at or above 50% of the maxinum level, from 2h after an aqueous HPMC suspension to 5.9h after use of Miglyol®. This again may be a reflection of the greater stability of the prodrug in the oily vehicle allowing absorption to continue for longer. The improvements in PK parameters seen with these oils are believed to be the result of reduced propensity for variable premature prodrug hydrolysis in the gut lumen.

Example 5 - Comparative effect of a Gelucire oil formulation of meptazinol PABA cabamate on the pharmacokinetics of meptazinol in the cynomolqus monkey.

[0101] Methods Groups of four or five male Cynomolgus monkeys were orally dosed in a crossover study design with meptazinol PABA carbamate HCI (2.0mg meptazinol equivs/kg) in aqueous suspension in hydroxypropyl methyl cellulose (HPMC) or in Gelucire 44/14 using a vehicle volume of 2ml_/kg. Femoral vein blood samples were subsequently collected into tubes containing 6.0mg/ml_ NaF, 1.75mg/ml_ K₂EDTA, 10ul 1 M citrate buffer pH 4.3 and 20mM 1 ,4 saccharolactone as prodrug stabilisers. Separated plasma samples were subjected to bioanalysis for meptazinol using a qualified LC/MS-MS bioanalytical method. Subsequent pharmacokinetic analysis was then undertaken using Win NonLin to generate the relevant PK parameters including AUC and T_1/2.

[0102] Results These are presented in Table 4 and show a good relative bioavailability of some 76% compared to a simple HPMC aqueous formulation. Importantly however was the much reduced variability in associated with the Gelucire formulation with a relative standard deviation of just 20% in AUC values compared to 44% after the aqueous formulation. This greater reproducibility was also reflected in the lesser variability in the Cmax value of just 29% cf. 61 % after the aqueous formulation. Similar reductions on variability in man would result in improved reproducibility of analgesic effects and consequently greater patient compliance.

Table 4: Pharmacokinetics of meptazinol in the monkey after oral dosing of 2 mg meptazinol equivalents /kg in Gelucire® or water

Pharmacokinetic

Gelucire 44/14 HPMC parameter

Mean^* SD CV Mean^** SD CV Cmax (ng/ml) 67 20 29 128 78 61

Tmax (h) 2 (2-2) 1 (0.5-3)

AUCinf (ng*h/ml) 203 42 20 267 1 17 44

Thalf (h) 1.4 0.1 10 1.1 0.1 1350percentCmax (h) 2.5 0.4 17 2.0 1.1 57

Frel(%) 76 16 20 100%

Claims

CLAIMS:

1. A pharmaceutical composition, comprising:

(a) an amino benzoic acid carbamate prodrug having the structure:

wherein: the term "drug" means a drug selected from the group consisting of: buprenorphine, butorphanol, dezocine, hydromorphone, ketobemidone, levorphanol, meptazinol, morphine, nalbuphine, nalorphine, naloxone, oxymorphone, pentazocine, tapentadol, apomorphine, curcumin, fenretinide, dextrorphan, L-dopa, dronabinol (Δ9 tetrahydrocannibinol), nabilone, oestriol, oestradiol, oestrone, raloxifene, rotigotine, and resveratrol;

R is independently selected at each occurrence from the group consisting of: hydroxy, carboxy, acetyl, cyano, cyanomethyl, nitro, amino, halogen, Ci_-6 alkyl, C-i_₆ haloalkyl, C-i_₆ alkoxy, C-i_₆ haloalkoxy, C₃.₆ cycloalkyl, aryl, aryl-C-i_₆ alkyl or C-i_₆ alkyl aryl;

R' is selected from the group consisting of: H and Ci_₆ alkyl; and n is from 0 to 3; or a pharmaceutically acceptable salt thereof; and

(b) a pharmaceutically acceptable oil-based delivery vehicle.

2. The pharmaceutical composition of claim 1 , wherein n is from 0 to 2.

3. The pharmaceutical composition of claim 1 or claim 2, wherein R is -OH.

4. The pharmaceutical composition of any of claims 1 to 3, wherein R' is selected from the group consisting of: H, Me and Et.

5. The pharmaceutical composition of any of claims 1 to 4, wherein COOR' is para- or meta- to the -NH- group.

6. The pharmaceutical composition of any preceding claim, wherein the pharmaceutical composition is in unit dosage form.

7. The pharmaceutical composition of any preceding claim, wherein the amino benzoic acid portion of the carbamate prodrug is selected from the group comprising: para-amino benzoic acid, 4-amino acid salicylic acid and 5-amino salicylic acid.

8. The pharmaceutical composition of any preceding claim, wherein the pharmaceutically acceptable oil is selected from the group comprising: almond oil, canola oil, castor oil, cotton seed oil, corn oil, (fractionated) coconut oil, olive oil, peanut oil (arachis oil), sesame seed oil, sunflower oil, medium chain mono and diglycerides, hydrogenated vegetable oil, medium chain triglycerides, mineral oil, a tocopherol, capric or caprylic triglycerides, glycerol stearate and Gelucire 44/14®.

9. The pharmaceutical composition of any preceding claim, wherein the pharmaceutically acceptable oil is 100% refined cotton seed oil.

10. The pharmaceutical composition of any of claims 1 to 8, wherein the pharmaceutically acceptable oil is 100% refined peanut oil.

1 1. The pharmaceutical composition of any of claims 1 to 8, wherein the pharmaceutically acceptable oil is 100% Capmul® MCMC-8, EP.

12. The pharmaceutical composition of any of claims 1 to 8, wherein the pharmaceutically acceptable oil is 100% Miglyol® 810 or 812.

13. The pharmaceutical composition of any of claims 1 to 8, wherein the pharmaceutically acceptable oil is 100% Gelucire 44/14®.

14. A pharmaceutical composition of the any preceding claims for use as a medicament.

15. A use of an oil-based delivery vehicle to prevent hydrolysis of an amino benzoic acid carbamate prodrug having the structure:

wherein: the term "drug" means a drug selected from the group consisting of: buprenorphine, butorphanol, dezocine, hydromorphone, ketobemidone, levorphanol, meptazinol, morphine, nalbuphine, nalorphine, naloxone, oxymorphone, pentazocine, tapentadol, apomorphine, curcumin, fenretinide, dextrorphan, L-dopa, dronabinol (Δ9 tetrahydrocannibinol), nabilone, oestriol, oestradiol, oestrone, raloxifene, rotigotine, and resveratrol; R is independently selected at each occurrence from the group consisting of: hydroxy, carboxy, acetyl, cyano, cyanomethyl, nitro, amino, halogen, Ci_₆ alkyl, Ci_₆ haloalkyl, C-i_₆ alkoxy, C-i_₆ haloalkoxy, C₃.₆ cycloalkyl, aryl, aryl-C-i_₆ alkyl or C-|.₆ alkyl aryl;

R' is selected from the group consisting of: H and C-i_₆ alkyl; and n is from 0 to 3.

16. A use of an oil-based delivery vehicle to preserve the chemical integrity of an amino benzoic acid carbamate prodrug having the structure:

R is independently selected at each occurrence from the group consisting of: hydroxy, carboxy, acetyl, cyano, cyanomethyl, nitro, amino, halogen, Ci_₆ alkyl, Ci_₆ haloalkyl, Ci_₆ alkoxy, Ci_₆ haloalkoxy, C₃.₆ cycloalkyl, aryl, aryl-Ci_₆ alkyl or Ci_₆ alkyl aryl;

R' is selected from the group consisting of: H and C-i_₆ alkyl; and n is from 0 to 3 to enable their active transport/absorption from the Gl tract.