compound and composition comprising oxycodone, method for reducing the potential abuse of said compo

专利摘要:
COMPOUND AND COMPOSITION UNDERSTANDING OXICODONE, A METHOD TO REDUCE THE POTENTIAL ABUSE OF THAT COMPOSITION, DOSAGE UNIT AND METHOD FOR ITS PREPARATION, AND METHOD FOR IDENTIFYING A COMPOUND AND A TRYPSIN INHIBITOR. The present invention relates to the modalities that provide Compound KC-8, N-1 - [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] -arginine-glycine malonic, or acceptable salts, solvates, and hydrates thereof. The present disclosure also provides compositions, and their methods of use, wherein the compositions comprise a prodrug, Compound KC-8, which provides controlled release of oxycodone. Such compositions can optionally provide a trypsin inhibitor that interacts with the enzyme that mediates the controlled release of oxycodone from the prodrug in order to attenuate the enzymatic cleavage of the prodrug.
公开号:BR112013017296B1
申请号:R112013017296-7
申请日:2012-01-09
公开日:2021-02-17
发明作者:Thomas E. Jenkins；Craig O. Husfeld
申请人:Signature Therapeutics, Inc.；
IPC主号:

专利说明:

[0001] The present invention relates to ketone-containing opioids, such as hydrocodone and oxycodone, which are susceptible to misuse, abuse or overdose. Consequently, it is necessary to control the use and access to these drugs. Controlling access to drugs is expensive to administer and can lead to denial of treatment for patients who are unable to report for dosing. For example, patients suffering from acute pain may be denied treatment with an opioid unless they have been admitted to a hospital. In addition, use control is often ineffective, leading to substantial morbidity and deleterious social consequences. summary
[0002] The modalities provide Compound KC-8, N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamino] -arginine-glycine malonic acid, shown below:
[0003] The modalities provide a composition, comprising N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] -arginine-glycine malonic acid, compound KC-8, shown below:
[0004] The disclosure provides Compound KC-8, a modified ketone opioid prodrug that provides the controlled release of oxycodone. In a ketone-modified opioid prodrug, a pro-portion is linked to oxycodone through the oxycodone's enolic oxygen atom. In a ketone-modified opioid prodrug, the hydrogen atom of the corresponding oxycodone enolic group is replaced by a covalent bond to a pro-portion. The proportions comprise an enzyme-cleavable moiety and a cyclizable spacer outlet group so that Compound KC-8 provides controlled release of oxycodone through cleavage of the enzyme followed by intramolecular cyclization. Compound KC-8 provides efficient oxycodone release when ingested.
[0005] The present disclosure also provides pharmaceutical compositions, and their methods of use, in which the pharmaceutical compositions comprise a prodrug, Compound KC-8, which provides controlled release of oxycodone through cleavage of the enzyme followed by intramolecular cyclization. Such compositions can optionally provide an inhibitor, such as a trypsin inhibitor, which interacts with the enzyme that mediates the controlled release of oxycodone from the prodrug in order to attenuate the enzymatic cleavage of the prodrug. The disclosure provides the enzyme as a gastrointestinal (Gl) enzyme, such as trypsin. Brief Description of the Figures
[0006] Figure 1 is a schematic representation of the effect of increasing the level of a trypsin inhibitor ("inhibitor", X-axis) in an FC parameter (for example, drug Cmax) (Y-axis) for a fixed dose of the prodrug. The effect of the inhibitor on a FC parameter of the prodrug can vary from undetectable, to moderate, to complete inhibition (that is, without detectable drug release). Figure 2 provides schematic graphs of drug concentration in plasma (Y-axis) over time. Panel A is a schematic of a pharmacokinetic profile (FC) after ingesting the drug with a trypsin inhibitor (dashed line) in which the drug Cmax is modified in relation to that of the drug without inhibitor (continuous line). Panel B is a schematic graph of an FC profile after ingesting drug with inhibitor (dashed line), in which drug Cmax and drug Tmax are modified relative to those of drug without inhibitor (continuous line). Panel C is a schematic graph of an FC profile after ingesting drug with inhibitor (dashed line), where drug Tmax is modified relative to that of drug without inhibitor (continuous line). Figure 3 provides schematic graphs that represent differential FC concentration-dose profiles that can result from dosing multiples of a unit dose (X-axis) of the present disclosure. Different FC profiles (as exemplified in this document for a representative parameter FC, drug Cmax (Y-axis)) can be provided by adjusting the relative amount of prodrug and trypsin inhibitor contained in a single unit dose or using a different prodrug or inhibitor in the unit dose. Figure 4 compares the mean plasma concentrations over time of oxycodone release following PO administration to rats of increasing doses of the compound KC-8 prodrug. Figure 5 compares the mean plasma concentrations over time of oxycodone release following PO administration to dogs of the compound KC-8 prodrug, compound KC-3 prodrug, OxyContin® tablets, or oxycodone HCl. Figure 6A and Figure 6B compare the mean plasma concentrations over time of oxycodone release following PO administration to rats of two doses of compound KC-8, each coded with increasing amounts of trypsin inhibitor Compound 109. Figure 7A compares the mean plasma concentrations over time of oxycodone release following PO administration to multiple unit dose rats of the compound Compound KC-8 in the absence of the trypsin inhibitor. Figure 7B compares the mean plasma concentrations over time of oxycodone release following PO administration to multiple unit dose unit rats of the compound KC-8 and trypsin inhibitor Compound 109. Figure 8 compares the average plasma concentrations over time of oxycodone release following PO administration to dogs of the prodrug Compound KC-8 in the absence or presence of trypsin inhibitor Compound 109. Terms
[0007] The following terms have the following meanings, unless otherwise indicated. Any undefined terms have their meanings recognized in the area.
[0008] "Unit dose" as used herein refers to a combination of a trypsin-cleavable prodrug (e.g., trypsin-cleavable prodrug) and a trypsin inhibitor. A "single unit dose" is a single unit of a combination of a trypsin cleavable prodrug (for example, trypsin cleavable prodrug) and a trypsin inhibitor, wherein the single unit dose provides a therapeutically effective amount of drug (i.e. , a sufficient amount of drug to cause a therapeutic effect, for example, a dose within the respective therapeutic window, or therapeutic range of the drug). "Multiple unit doses" or "multiples of a unit dose" or "multiple of a unit dose" refers to at least two single unit doses.
[0009] "Gastrointestinal enzyme" or "Gl enzyme" refers to an enzyme located in the gastrointestinal tract (Gl), which covers anatomical sites from the mouth to the anus. Trypsin is an example of a Gl enzyme.
[0010] "Gastrointestinal enzyme cleavable moiety" or "G1 enzyme cleavable moiety" refers to a group comprising a site susceptible to cleavage by a Gly enzyme. For example, a "trypsin-dividing moiety" refers to a group comprising a site susceptible to trypsin cleavage.
[0011] "Gastrointestinal enzyme inhibitor" or "Gl enzyme inhibitor" refers to any agent capable of inhibiting the action of a gastrointestinal enzyme on a substrate. The term also encompasses salts of gastrointestinal enzyme inhibitors. For example, a "trypsin inhibitor" refers to any agent capable of inhibiting the action of trypsin on a substrate.
[0012] "Patient" includes humans, as well as other mammals, such as cattle, zoo animals and companion animals, such as a cat, dog or horse.
[0013] "Pharmaceutical composition" refers to at least one compound and may further comprise a pharmaceutically acceptable carrier, with which the compound is administered to a patient.
[0014] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which or into which a compound is administered.
[0015] "Pharmaceutically acceptable salt" refers to a salt of a compound that has the desired pharmacological activity of the compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chloro sulfonic acid, 2-naphthalenesulfonic acid, 4-tuluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, suifuric laurii, gluconic acid, glutamic acid, hydroxinaftoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanamine, N-methylglucamine and the like.
[0016] "Pharmacodynamic profile (FD)" refers to a profile of the efficacy of a drug in a patient (or subject or user), which is characterized by FD parameters. "FD parameters" include "Drug Emax" (maximum drug efficacy), "Drug EC50" (50% Emax drug concentration) and side effects.
[0017] "FC Parameter" refers to a measurement of drug concentration in blood or plasma, such as: 1) "Drug Cmax", the maximum drug concentration achieved in blood or plasma; 2) "Tmax of drug", the time elapsed after ingestion to reach Cmax; and 3) "drug exposure" means the total drug concentration present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a drug release time course at over a selected period of time (t). The modification of one or more FC parameters provides a modified FC profile.
[0018] "FC profile" refers to a drug concentration profile in blood or plasma. This profile can consist of a drug concentration ratio over time (that is, a "concentration-time FC profile") or a drug concentration relationship versus the number of doses ingested (that is, a "FC profile and concentration- dose"). An FC profile is characterized by FC parameters.
[0019] "Prevent" or "prevention" or "prophylaxis" refers to a reduction in the risk of a condition occurring, such as pain.
[0020] "Prodrug" refers to a derivative of an active agent that requires a transformation inside the body to release the active agent. In certain embodiments, the transformation is an enzymatic transformation. In certain modalities, the transformation is a cyclization transformation. In certain embodiments, the transformation is a combination of an enzymatic transformation and a cyclization reaction. Prodrugs are often, though not necessarily, pharmacologically inactive until they become an active agent.
[0021] "Pro-portion" refers to a form of protection group that, when used to mask a functional group into an active agent, converts the active agent into a prodrug. Typically, the proportions will be connected to the drug via binding (s) that are (are) cleaved (s) by enzymatic or non-enzymatic means in vivo.
[0022] "Solvate" as used herein refers to a complex or aggregate formed by one or more molecules of a solute, for example, a prodrug or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute to solvent. Representative solvents include, by way of example, water, methanol, ethanol, isopropanol, acetic acid and the like. When the solvent is water, the solvate formed is a hydrate.
[0023] "Therapeutically effective amount" means the amount of a compound (eg, prodrug) that, when administered to a patient to prevent or treat a condition, such as pain, is sufficient to effect such treatment. The "therapeutically effective amount" will vary, depending on the compound, the condition and its severity and the age, weight, etc., of the patient.
[0024] "Treating" or "treating" any condition, such as pain, refers, in certain modalities, to improving the condition (that is, stopping or reducing the development of the condition). In certain modalities "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the patient. In certain embodiments, "treating" or "treatment" refers to the inhibition of the condition, either physically (for example, stabilization of a discernible symptom), physioiogically (for example, stabilization of a physical parameter) or both. In certain modalities, "treat" or "treatment" refers to delaying the onset of the condition. Detailed Description
[0025] Before the present invention is further described, it is to be understood that this invention is not limited to the particular embodiments described, as these can obviously vary. It is also to be understood that the terminology used in this document is intended to describe only particular modalities, and was not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[0026] It should be noted that, as used here and in the attached claims, the singular forms "one", "one" and "o", "a" include plural referents, unless the context clearly dictates otherwise. It should also be noted that claims can be outlined to exclude any optional elements. As such, it is intended that this statement serves as an antecedent basis for the use of exclusive terminology, such as "only", "only" and the like, related to the recitation of claim elements, or the use of a "negative" limitation.
[0027] It should be understood that, as used herein, the term "an" entity refers to one or more of that entity. For example, a compound refers to one or more compounds. As such, the terms "one", "one", "one or more" and "at least one" can be used interchangeably. Similarly, the terms "comprising", "including" and "possessing" can be used interchangeably.
[0028] The publications discussed here are provided for their disclosure only prior to the date of registration of this application. Nothing presented here should be considered as an admission that the present invention is not entitled to anticipate these publications by virtue of a previous invention. In addition, the publication dates provided may differ from the actual publication dates, and it may be necessary to confirm them independently.
[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning commonly understood by the person skilled in the field to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials will now be described. All publications mentioned here are incorporated by reference here to disclose and describe the methods and / or materials in connection with which the publications are cited.
[0030] Unless noted to the contrary, the methods and techniques of the present embodiments are generally implemented in accordance with conventional methods well known in the art and as described in various general and more specific references which are cited and discussed throughout the present specification. See, for example, Loudon, "Organic Chemistry", Fourth Edition, New York: Oxford University Press, 2002, pages 360361, 1084-1085; Smith and March, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", Fifth Edition, Wiley-Interscience, 2001.
[0031] The nomenclature used here to designate the compounds in question is illustrated in the Examples presented here. In certain circumstances, this nomenclature is derived using commercially available AutoNom software (MDL, San Leandro, Calif.).
[0032] It is appreciated that certain features of the invention, which are, for the sake of clarity, described in the context of separate modalities, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for the sake of brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of modalities relating to the chemical groups represented by the variables are specifically covered by the present invention and are disclosed here as if each and all combinations were individually and explicitly disclosed, to the extent that those combinations cover compounds that are stable compounds (i.e. , compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombination of the chemical groups listed in the modalities that describe these variables are also specifically covered by the present invention, and are disclosed here as if each and all of these subcombination of chemical groups were individually and explicitly disclosed here. General Synthetic Procedures
[0033] Many general references are available that provide schematic graphs and commonly known chemical synthesis conditions useful for synthesizing the disclosed compounds (see, for example, Smith and March, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", Fifth Edition, Wiley -lnterscience, 2001; or Vogel, "A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis", Fourth Edition, New York: Longman, 1978).
[0034] The compounds described here can be purified by any of the means known in the art, including chromatographic media, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases, as well as ionic resins. See, for example, "Introduction to Modern Liquid Chromatography", 2nd Edition, editors L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and "Thin Layer Chromatography", editor E. Stahl, Springer-Verlag, New York, 1969.
[0035] During any of the processes for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the respective molecules. This can be achieved through conventional protection groups as described in standard works, such as TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2006. Protective groups can be removed at a convenient subsequent stage using methods known in the art.
[0036] The compounds described herein can contain one or more chiral centers and / or double bonds and, therefore, can exist in the form of stereoisomers, such as isomers in double bonds (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds, including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, are included in the description of the compounds presented herein. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art. The compounds can also exist in various tautomeric forms, including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures represented here encompass all possible tautomeric forms of the illustrated compounds.
[0037] The described compounds also include isotopically labeled compounds, where one or more atoms have an atomic mass different from the atomic mass conventionally present in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, 2H, 3H, 11C, 13C, 14C, 15N, 180, 170, etc. The compounds can exist in unsolvated forms as well as solvated forms including hydrated forms. In general, the compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated here and are intended to be within the scope of this disclosure. Representative modalities
[0038] Various modalities will now be mentioned in detail. It will be understood that the invention is not limited to these modalities. On the contrary, it is intended to cover alternatives, modifications and equivalents that may be included in the spirit and scope of the permitted claims.
[0039] The modalities provide Compound KC-8, N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] -arginine-glycine malonic acid, shown below:
[0040] The modalities provide a composition, comprising N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] -arginine-glycine malonic acid, Compound KC-8, shown below:
[0041] The disclosure provides Compound KC-8, a modified ketone opioid prodrug that provides the controlled release of oxycodone. In a ketone-modified opioid prodrug, a pro-portion is linked to oxycodone through the oxycodone's enolic oxygen atom. In a ketone-modified opioid prodrug, the hydrogen atom of the corresponding oxycodone enolic group is replaced by a covalent bond to a pro-portion.
[0042] In Compound KC-8, the pro-portion comprises a cyclizable spacer outlet group and a cleavable portion. In KC-8 Compound, the ketone-modified oxycodone prodrug is a corresponding compound in which the enolic oxygen atom has been replaced by a spacer leaving group carrying a nucleophilic nitrogen that is protected with an enzyme-cleavable moiety, the group configuration spacer outlet and nucleophilic nitrogen so that, after enzymatic cleavage of the cleavable portion, the nucleophilic nitrogen is able to form a cyclic urea, releasing the compound from the spacer outlet group in order to provide oxycodone.
[0043] The enzyme capable of cleaving the enzyme-cleavable moiety may be a peptidase, also referred to as a protease - the pro-portion comprising the enzyme-cleavable moiety being linked to nu-deophilic nitrogen via an amide (for example, a peptide: - NHC (O) -) on. In some embodiments, the enzyme is a digestive enzyme for a protein. The disclosure provides an enzyme being a G1 enzyme, such as trypsin and the enzyme cleavable moiety being an enzyme cleavable G1 moiety, such as a trypsin cleavable moiety.
[0044] The corresponding prodrug provides the controlled release of oxycodone, activated after administration. The prodrug requires enzymatic cleavage to initiate the release of oxycodone, and thus the rate of oxycodone release depends on both rates of enzymatic cleavage and the rate of cyclization. Compound KC-8 provides efficient controlled release of oxycodone due to a combination of a rapid rate of enzyme cleavage and a rapid rate of intramolecular cyclization. The prodrug is configured so as not to provide excessively high levels in the plasma of the active drug if administered improperly, and cannot be easily decomposed to give rise to the active drug in a way other than enzymatic cleavage followed by controlled cyclization,
[0045] The cyclic group formed when the oxycodone is released is suitably pharmaceutically acceptable, in particular pharmaceutically acceptable cyclic urea. It will be appreciated that cyclic ureas are, in general, very stable and have low toxicity. General Synthetic Procedures for Compounds
[0046] Representative synthetic schemes for the compounds disclosed in this document are shown below. Compound KC-8 can be synthesized using the disclosed methods. Representative synthetic schemes
[0047] A representative synthesis for compound S-104 is shown in Scheme 1. In Scheme 1, for Compound KC-8, n is 3; the first and third twin R1 and R2 are hydrogen; the second twin R1 and R2 are methyl; R5 is methyl; and PG1 is an amino protection group.
[0048] In Scheme 1, Compound S-100 is a commercially available starting material. Alternatively, Compound S-100 can be synthesized through a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods.
[0049] With continued reference to Scheme 1, Compound S-100 is protected in the amine group with a trifluoroacetyl group to form Compound S-101. A trifluoroacetyl group can be formed by reacting using reagents, such as ethyl trifluoroacetate, trifluoroacetyl chloride, or 1,1,1-trichloro-3,3,3-trifluoroacetone.
[0050] Compound S-101 is protected on the other amine group to form Compound S-102, where PG1 is an amine protecting group. Amine protecting groups can be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2006. Representative amino protecting groups include, but are not limited to, formyl groups; acyl groups, for example, al-kanoyl groups, such as acetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr) and 1,1-di- (4'-methoxyphenyl) methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and others.
[0051] In certain embodiments, PG1 is Boc. The conditions for forming Boc groups in Compound S-102 can be found in Greene and Wuts. One method is the reaction of Compound S-101 with di-tert-butyl carbonate. The reaction can optionally be carried out in the presence of an activating agent, such as DMAP. In Scheme 1, in certain modalities, the trifluoroacetyl protection group and PG1, such as Boc, are orthogonal protection groups.
[0052] With continued reference to Scheme 1, the trifluoroacetyl group in Compound S-102 is deprotected to form Compound S-103. Conditions for removing the trifluoroacetyl group can be found in Greene and Wuts. Methods for removing the trifluoroacetyl group include hydrolysis of Compound S-102. Certain conditions for hydrolysis include reaction with sodium hydroxide or lithium hydroxide.
[0053] With continued reference to Scheme 1, the group R5 is added on Compound S-103 to form Compound S-104. The addition of the R5 group over the amine group of Compound S-103 can be facilitated with the use of protection / activation groups. In certain embodiments, a nosyl group on the amino group of Compound S-103 is added prior to the addition of Group R5. A nosila group can be added using nosila chloride.
[0054] In certain embodiments, Group R5 is methyl and is added through the use of methyl iodide. After the addition of Group R5, the protection / activation group can be removed to produce Compound S-104. For example, the removal of the nosila group can be performed with thiophenol.
[0055] A representative synthesis for compound S-202 is shown in Scheme 2. In Scheme 2, for Compound KC-8, Ra is hydroxyl; n is 3; the first and third twin R1 and R2 are hydrogen; the second twin R1 and R2 are methyl; R5 is methyl; and PG1 is an amine protection group
[0056] In Scheme 2, Compound S-200 is a commercially available starting material. Alternatively, Compound S-200 can be semi-synthetically derived from natural materials or synthesized through a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods.
[0057] With continued reference to Scheme 2, Compound S-200 is reacted with Compound S-104 to form Compound S-201. In this reaction, Compound S-200 reacts with the amino group of Compound S-104 with a carbamate-forming reagent to produce Compound S-201. Suitable carbamate-forming reagents include chloroformates, such as 4-nitrophenyl chloroform.
[0058] With continued reference to Scheme 2, the protecting group PG1 is removed from Compound S-201 to form Compound S-202. Conditions for the removal of amino groups can be found in Greene and Wuts. When PG1 is a Boc group, the protecting group can be removed under acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
[0059] A representative synthesis for compound S-303 is shown in Scheme 3. In Scheme 3, for Compound KC-8, Ra is hydroxyl; n is 3; the first and third twin R1 and R2 are hydrogen; the second twin R1 and R2 are methyl; R5 is methyl; R6 is the side chain of arginine; and PG2 is an optional amino protection group.
[0060] With reference to Scheme 3, Compound S-202 reacts with Compound S-301 to form Compound S-302 in a peptide coupling reaction. In certain embodiments, R6 is the side chain of arginine and is optionally protected. Protective groups for the side chain of arginine are known to those skilled in the art and can be found in Greene and Wuts. In certain circumstances, the protection group for the arginine side chain is a sulfonyl-type protection group, such as 2,2,4,6,7-pentamethyldihydrobenzofuran (Pbf). Other protection groups include 2,2,5,7,8-pentamethylchroman (Pmc) and 1,2-dimethylindol-3-sulfonyl (MIS).
[0061] A peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional reactive coupling conditions, typically in the presence of a trialkylamine, such as ethyldiisopropylamine or diisopropylethylamine (DIE-A). Coupling reagents suitable for use include, by way of example, carbodiimides, such as ethyl-3- (3-dimethylamino) propylcarbo-diimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and the like, and other reagents of well-known coupling, such as N, N'-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), benzotriazole-1-yloxy-tris (dimethylamino) phosphonium (BOP) hexa-fluorophosphate (BOP), hexa - 0- (7-azabenzotriazol-1-yl) fluorophosphate -N, N, N, N ', N'-tetramethyluronium (HA-TU) and the like. Optionally, well-known coupling promoters such as N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAT), N, N-dimethyl-aminopyridine (DMAP) and the like can be employed in this reaction . Typically, this coupling reaction is conducted at a temperature ranging from about 0 ° C to about 60 ° C for about 1 to about 72 hours in an inert diluent, such as THF or DMF. In certain circumstances, Compound S-202 reacts with Compound S-301 to form Compound S-302 in the presence of HATU.
[0062] With continued reference to Scheme 3, Compound S-302 is transformed into Compound S-303 with the removal of the amine protecting group. Conditions for the removal of amino groups can be found in Greene and Wuts. When PG2 is a Boc group, the protecting group can be removed under acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
[0063] A representative synthesis for compound S-401 is shown in Scheme 4. In Scheme 4, for Compound KC-8, Ra is hydroxyl; n is 3; the first and third twin R1 and R2 are hydrogen; the second twin R1 and R2 are methyl; R5 is methyl; R6 is the side chain of arginine; R7 is the glycine side chain; and R8 is the malonyl group.
[0064] In Scheme 4, Compound S-400 is a commercially available starting material. Alternatively, Compound S-400 can be synthesized through a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods.
[0065] Referring to Scheme 4, Compound S-303 reacts with Compound S-400 to form Compound S-401 in a peptide coupling reaction. A peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional reactive coupling conditions, typically in the presence of a trialkylamine, such as ethyldiisopropylamine or diisopropylethylamine (DIEA). Coupling reagents suitable for use include, by way of example, carbodiimides, such as ethyl-3- (3-dimethylamino) propylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), diisopropylcarbo-diimide (DIC) and the like, and other reagents of well-known coupling, such as Ν, Ν'-carbonyldiimidazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), benzotriazole-1-yloxy-tris (dimethylamino) phosphonium (BOP) hexafluorophosphate (OOP) hexafluorophosphate - (7-azabenzotriazol-1-yl) -N, N, N, N ', N'-tetramethyl-uronium (HATU) and the like. Optionally, well-known coupling promoters such as N-hydroxysucci-nimide, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzothazoi (HOAT), Ν, Ν-dimethylaminopyridine (DMAP) and the like can be employed in this reaction . Typically, this coupling reaction is conducted at a temperature ranging from about 0 ° C to about 60 ° C for about 1 to about 72 hours in an inert diluent, such as THF or DMF. In certain circumstances, Compound S-303 reacts with Compound S-400 to form Compound S-401 in the presence of HATU.
[0066] In certain circumstances in Scheme 4, when Compound S-400 is reacted with Compound S-303 with R8 as hydrogen, the group R8 as a malonyl group is added after the amino acid coupling reaction. A malonyl group can be attached via a reaction with mono-tert-butyl malonate. The reaction using mono-tert-butyl malonate can be supported with the use of activation reagents, such as symmetric anhydrides, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium (HBTU), dicyclohexylcarbodiimide (DCC) diisopropylcarboiimide (DIC) / 1-hydrobenzotriazole (HOBt), and benzotriazo! e-1-yl-oxytris (dimethylamino) phosphonium (BOP). A malonyl group can also be attached using N-carboxymethyl malonic acid tert-butyl ester.
[0067] With continued reference to Scheme 4, the removal of other protection groups can be carried out if other protection groups are used, such as protection groups present in the R6 portion. Conditions for the removal of other protecting groups depend on the identity of the protecting group and are known to those skilled in the art. Conditions can also be found in Greene and Wuts. Other representative synthetic schemes
[0068] A representative synthesis for compound S-503 is shown in Scheme 5. In Scheme 5, for Compound KC-8, n is 3; the first and third twin R1 and R2 are hydrogen; the second twin R1 and R2 are methyl; R5 is methyl; and PG1 and PG2 are optional amino protection groups.
[0069] In Scheme 5, Compound S-500 is a commercially available starting material. Alternatively, Compound S-500 can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods.
[0070] With continued reference to Scheme 5, Compound S-500 is protected in the amine group to form Compound S-501, where PG1 and PG2 are amine protecting groups. Amine protecting groups can be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2006. Representative amino protecting groups include, but are not limited to, formyl groups; acyl groups, for example, alkanoyl groups, such as acetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxy-carbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr) and 1,1-di- (4'-methoxyphenyl) methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and others.
[0071] In certain embodiments, PG1 and PG2 are Boc groups. The conditions for forming Boc groups in Compound S-501 can be found in Greene and Wuts. One method is the reaction of Compound S-500 with dicarbone-to di-tert-butyl. The reaction can optionally be carried out in the presence of an activating agent, such as DMAP.
[0072] With continued reference to Scheme 5, the carboxybenzyl group in Compound S-501 is deprotected to form Compound S-502. Conditions for the removal of the carboxybenzyl group can be found in Greene and Wuts. Methods for removing the carboxybenzyl group include hydro-hydrogenolysis of Compound S-501 or treatment of Compound S-501 with H-Br. One method for removing the carboxybenzyl group is the reaction of Compound S-501 with hydrogen and palladium.
[0073] With continued reference to Scheme 5, Compound S-502 is reacted with phosgene to form Compound S-503. Reaction with phosgene forms an acyl chloride in the amine group of Compound S-502. Other reagents can act as substitutes for phosgene, such as diphosgene or tri-phosgene.
[0074] A representative synthesis for compound S-602 is shown in Scheme 6. In Scheme 6, for Compound KC-8, Ra is hydroxyl; n is 3; the first and third twin R1 and R2 are hydrogen; the second R1 and R2 twin are methyl; R5 is methyl; and PG1 and PG2 are optional amino protection groups.
[0075] In Scheme 6, Compound S-600 is a commercially available starting material. Alternatively, Compound S-600 can be semi-synthetically derived from natural materials or synthesized via a variety of different synthetic pathways using commercially available starting materials and / or starting materials prepared by conventional synthetic methods.
[0076] With continued reference to Scheme 6, Compound S-600 is reacted with Compound S-503 to form Compound S-601. In this reaction, the Enolate of Compound S-600 reacts with the acyl chloride of Compound S-503 to form a carbamate.
[0077] With continued reference to Scheme 6, the optional protection groups PG1 and PG2 are removed from Compound S-601 to form Compound S-602. Conditions for the removal of amino groups can be found in Greene and Wuts. When PG1 and / or PG2 are Boc groups, the protecting groups can be removed under acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
[0078] Compound S-602 can be used as in the above schemes, such as Schemes 3 and 4, to prepare Compound KC-8.
[0079] As described in more detail here, the disclosure provides processes and intermediates useful for the preparation of compounds of the present disclosure, or a salt or solvate or stereoisomer thereof. Accordingly, the present disclosure provides a process for preparing a compound of the present disclosure, the process of which involves: contact a compound of formula:
[0080] Accordingly and as described in more detail here, the present disclosure provides a process for preparing a compound of the present disclosure, the process of which involves: contact a compound of formula:
[0081] Accordingly and as described in more detail here, the present disclosure provides a process for preparing a compound of the present disclosure, the process of which involves: contact a compound of formula:
[0082] In one situation, the above processes may also involve a step of forming a salt of a compound of the present disclosure. The modalities are addressed to the other processes described here; and the product prepared by any of the processes described here. Trypsin Inhibitors
[0083] As disclosed in this document, the present disclosure also provides pharmaceutical compositions, and methods of use thereof, in which the pharmaceutical compositions comprise a prodrug, Compound KC-8, which provides controlled release of oxycodone through enzyme divage followed by intramolecular cyclization. and a trypsin inhibitor that interacts with the enzyme that mediates the release of oxycodone from the enzyme-mediated prodrug in order to attenuate the enzyme divage of the prodrug. This disclosure provides the enzyme being trypsin.
[0084] As used herein, the term "trypsin inhibitor" refers to any agent capable of inhibiting the action of trypsin on a substrate. The term "trypsin inhibitor" also encompasses salts of trypsin inhibitors. The ability of an agent to inhibit trypsin can be measured using assays well known in the art. For example, in a typical assay, one unit corresponds to the amount of inhibitor that reduces trypsin activity in a benzoyl-L-arginine ethyl ester (BAEE-U) unit. A BAEE-U is the amount of enzyme that increases the absorbance at 253 nm by 0.001 per minute at pH 7.6 and 25 ° C. See, for example, K. Ozawa, M. Laskowski, 1966, J. Biol. Chem. 241, 3955, and Y. Birk, 1976, Meth. Enzymol. 45, 700. In certain cases, a trypsin inhibitor may interact with an active site of trypsin, such as the S1 pouch and the S3 / 4 pouch. The S1 pouch has an aspartate residue that has an affinity for a positively charged portion. The S3 / 4 pouch is a hydrophobic pouch. The disclosure provides specific trypsin inhibitors and nonspecific serine protease inhibitors.
[0085] Many trypsin inhibitors are known in the art, those specific for trypsin and those that inhibit trypsin and other proteases, such as chypsis. The disclosure provides trypsin inhibitors which are proteins, peptides and small molecules. The disclosure provides trypsin inhibitors that are irreversible or reversible inhibitors. The disclosure provides trypsin inhibitors that are competitive inhibitors, non-competitive inhibitors or non-competitive inhibitors. The disclosure provides natural, synthetic or semi-synthetic trypsin inhibitors.
[0086] Trypsin inhibitors can be derived from a variety of animal or vegetable sources: for example, soybeans, corn, lima beans and other beans, pumpkin, sunflower, pancreas and bovine lung and other animals, egg white from chickens and turkeys, infant formulation based on soy and mammalian blood. Trypsin inhibitors can also be microbial in origin: for example, antipain; see, for example, H. Umezawa, 1976, Meth. Enzymol. 45, 678. The trypsin inhibitor can also be a mimetic of arginine or lysine or another synthetic compound: for example, aryl-guanidine, benzamidine, 3,4-dichloroisocoumarin, diisopropylfluorophosphate, ga-bexate mesylate, fluoride phenylmethanesulfonyl, or substituted or analogous versions thereof. In certain embodiments, trypsin inhibitors comprise a covalently modifiable group, such as a chlorocetane moiety, an aldehyde moiety or an epoxide moiety. Other examples of trypsin inhibitors are aprotinin, camostat and pentamidine.
[0087] As used here, an arginine or lysine mimetic is a compound that is capable of binding to the P1 bag of trypsin and / or interfering with the function of the active site of trypsin. The arginine or lysine mimic can be a divable or non-cleavable portion.
[0088] In one embodiment, the trypsin inhibitor is derived from soy. Trypsin inhibitors derived from soy (Glycine max) are readily available and are considered safe for human consumption. They include but are not limited to SBTI, which inhibits trypsin, and Bowman-Birk inhibitor, which inhibits trypsin and chymotrypsin. These trypsin inhibitors are available, for example, from Sigma-Aldrich, St. Louis, MO, USA.
[0089] It will be appreciated that the pharmaceutical composition according to the modalities can additionally comprise one or more different trypsin inhibitors.
[0090] As stated above, a trypsin inhibitor can be an arginine or lysine mimetic or other synthetic compound. In certain embodiments, the trypsin inhibitor is an arginine mimetic or a lysine mimetic, wherein the arginine mimetic or lysine mimetic is a synthetic compound.
[0091] Certain trypsin inhibitors include compounds of the formula:
[0092] A description of methods for preparing Compound 101, Compound 102, Compound 103, Compound 104, Compound 105, Compound 107, and Compound 108 is provided in PCT International Publication Number WO 2010 / 045599A1, published April 22, 2010, which is incorporated in this document in its entirety as a reference. Compounds 106, Compound 109, and Compound 110 are commercially available, for example, from Sigma-Aldrich, St. Louis, MO, USA.
[0093] In certain embodiments, the trypsin inhibitor is SBTI, BBSI, Compound 101, Compound 106, Compound 108, Compound 109 or Compound 110. In certain embodiments, the trypsin inhibitor is camostat.
[0094] In certain embodiments, the trypsin inhibitor is a compound of the formula T1:
[0095] In certain embodiments, the trypsin inhibitor is a compound selected from the following:
[0096] In certain embodiments, the trypsin inhibitor is a compound of the formula T-ll:
[0097] In certain embodiments, in formula T-ll, Rt1 is guanidine or amidine. In certain embodiments, in the formula T-ll, Rt1 is - (CH2) mC (O) -O- (CH2) mC (O) -N-Rn1Rn2, where m is one and Rn1 and Rn2 are methyl.
[0098] In certain embodiments, the trypsin inhibitor is a compound of the formula T-ll:
[0099] In certain embodiments, in the formula T-II, Rt2 is guanidine or amidine. In certain embodiments, in the formula T-lll, Rt2 is - (CH2) mC (O) -O- (CH2) mC (O) -N-Rn1Rn2, where m is one and Rn1 and Rn2 are methyl.
[0100] In certain embodiments, the trypsin inhibitor is a compound of formula T-IV:
[0101] In certain embodiments, the trypsin inhibitor is Compound 110 or a bis-arylamidine variant thereof; see, for example, J.D. Geratz, M.C.-F. Cheng and R.R.Tidwell (1976) J Med. Chem. 19, 634-639.
[0102] It is to be appreciated that the invention also includes inhibitors of other enzymes involved in the assimilation of proteins that can be used in combination with Compound KC-8 to attenuate an oxycodone release from the prodrug. Combinations of Prodrug and Trypsin Inhibitor
[0103] As discussed above, the present disclosure provides pharmaceutical compositions comprising a trypsin inhibitor and Compound KC-8, a ketone-modified oxycodal prodrug, which comprises a pro-portion comprising a trypsin-cleavable portion which, when cleaved, facilitates the prodrug. of oxycodone. Examples of compositions containing Compound KC-8 and a trypsin inhibitor are described below.
[0104] The embodiments provide a pharmaceutical composition, which comprises a compound of Formula T-1 to T-IV and Compound KC-8, or a pharmaceutically acceptable salt thereof. The embodiments provide a pharmaceutical composition, comprising Compound 109 and Compound KC-8, or a pharmaceutically acceptable salt thereof.
[0105] Certain embodiments provide a combination of Compound KC-8 and a trypsin inhibitor, in which the trypsin inhibitor is shown in the table below.
[0106] The disclosure provides for Compound KC-8 and another prodrug or drug included in a pharmaceutical composition. This prodrug or drug provides additional analgesia or other benefits. Examples include opioids, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics. In one embodiment, Compound KC-8 must be combined with an opioid antagonist prodrug or drug. Other examples include drugs or prodrugs that have different benefits or in addition to analgesia. The embodiments provide a pharmaceutical composition, which comprises Compound KC-8 and acetaminophen, or a pharmaceutically acceptable salt thereof.
[0107] Such compositions may also comprise a trypsin inhibitor. In certain embodiments, the trypsin inhibitor is selected from SBTI, BBSI, Compound 101, Compound 106, Compound 108, Compound 109, and Compound 110. In certain embodiments, the trypsin inhibitor is Compound 109. In certain embodiments, the trypsin inhibitor is camostat.
[0108] In certain embodiments, the pharmaceutical composition can comprise Compound KC-8, a non-opioid drug and at least one opioid or opioid prodrug. Pharmaceutical Compositions and Methods of Use
[0109] As disclosed in this document, the embodiments provide a composition, which comprises N-1- [3- (oxycodone-6-enoyl-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] -arginine-glycine-malonic acid, Compound KC-8. The pharmaceutical composition according to the modalities can also comprise a pharmaceutically acceptable carrier. The composition is conveniently formulated in a form suitable for oral administration (including buccal and sublingual), for example, in the form of a tablet, capsule, thin film, powder, suspension, solution, syrup, dispersion or emulsion. The composition may contain conventional components in pharmaceutical preparations, for example, one or more carriers, binders, lubricants, excipients (for example, to impart controlled release characteristics), pH modifiers, sweeteners, bulking agents, coloring agents or other agents active.
[0110] Patients can be humans, as well as other mammals, such as cattle, zoo animals and companion animals, such as a cat, dog or horse.
[0111] In another aspect, the modalities provide a pharmaceutical composition as described above for use in the treatment of pain. The pharmaceutical composition according to the modalities is useful, for example, in the treatment of a patient suffering from, or at risk of, suffering from pain. Accordingly, the present disclosure provides methods of treating or preventing pain in a subject, whose methods involve administering to the subject a disclosed composition. The present disclosure provides a composition disclosed for use in therapy or prevention, or as a medicine. The present disclosure also provides for the use of a disclosed composition for the manufacture of a medicament, in particular for the manufacture of a medicament intended for the treatment or prevention of pain.
[0112] The compositions of the present disclosure can be used in the treatment or prevention of pain including, but not limited to, acute pain, chronic pain, neuropathic pain, acute traumatic pain, arthritic pain, osteoarthritic pain, rheumatoid arthritic pain, musculoskeletal pain, post-pain -Dental surgery, dental pain, myofascial pain, pain due to cancer, visceral pain, diabetic pain, muscle pain, post-herpetic neuronal pain, chronic pelvic pain, pain due to endometriosis, pelvic inflammatory pain and pain related to childbirth. Acute pain includes, but is not limited to, acute traumatic pain or post-surgical pain. Chronic pain includes, but is not limited to, neuropathic pain, arthritic pain, osteoarthritic pain, rheumatoid arthritic pain, musculoskeletal pain, dental pain, myofascial pain, cancer pain, diabetic pain, visceral pain, muscle pain, post-herpetic neuralgic pain, chronic pelvic pain, pain due to endometriosis, pelvic inflammatory pain and back pain.
[0113] The present disclosure also provides for the use of Compound KC-8 in the treatment of pain. The present disclosure also provides for the use of Compound KC-8 in the prevention of pain.
[0114] The present disclosure provides for the use of Compound KC-8 in the manufacture of a pain medication. The present disclosure provides for the use of Compound KC-8 in the manufacture of a pain-preventing drug.
[0115] In another aspect, the modalities provide a method for treating pain in a patient in need of it, which comprises administering an efficient amount of a pharmaceutical composition as described above in this document. In another aspect, the modalities provide a method for preventing pain in a patient in need of it, which comprises administering an efficient amount of a pharmaceutical composition as described above in this document.
[0116] The amount of composition disclosed in this document to be administered to a patient to be effective (that is, to provide blood levels of oxycodone sufficient to be effective in the treatment or prophylaxis of pain) will be dependent on the bioavailability of the specific composition, the susceptibility of the specific composition the activation of the enzyme in the intestine, as well as other factors, such as the species, age, weight, sex, and condition of the patient, mode of administration and the opinion of the prescribing physician. If the composition also comprises a trypsin inhibitor, the amount of the composition disclosed in this document to be administered to a patient should also depend on the amount and potency of the trypsin inhibitor present in the composition. In general, the dose of the composition can be such that Compound KC-8 is in a range from 0.01 milligram of prodrug per kilogram to 20 milligrams of prodrug per kilogram (mg / kg) of body weight. For example, a composition comprising Compound KC-8 can be administered at a dose equivalent to administration of free oxycodone in a range from 0.02 to 0.5 mg / kg of body weight or 0.01 mg / kg to 10 mg / kg body weight or 0.01 to 2 mg / kg body weight. In one embodiment, the composition can be administered at a dose such that the level of oxycodone reached in the blood is in a range from 0.5 ng / ml to 10 ng / ml.
[0117] As disclosed above, the present disclosure also provides pharmaceutical compositions which comprise a trypsin inhibitor and Compound KC-8, a phenol-modified oxycodone prodrug, which comprises the pro-portion comprising a trypsin-cleavable portion which, when cleaved, facilitates the release of oxycodone. In these pharmaceutical compositions, the amount of a trypsin inhibitor to be administered to the patient to be efficient (i.e., to attenuate the release of oxycodone when administration of Compound KC-8 alone should lead to overexposure of oxycodone) will depend on the effective dose of Compound KC-8 and the potency of the particular trypsin inhibitor, as well as other factors, such as the species, age, weight, sex and condition of the patient, mode of administration and opinion of the prescribing physician. In general, the dose of trypsin inhibitor can be in a range from 0.05 mg to 50 mg per mg of Compound KC-8. In one embodiment, the dose of trypsin inhibitor can be in a range from 0.001 mg to 50 mg per mg of Compound KC-8. In one embodiment, the dose of trypsin inhibitor can be in a range from 0.01 nanomol to 100 micromoles per micromole of Compound KC-8. Representative Modalities of Dose Units of KC-8 Prodrug Compound and Trypsin Inhibitor Having a Desired Pharmacokinetic Profile
[0118] The embodiments include a composition comprising (a) a prodrug comprising oxycodone covalently linked via enolic oxygen to a pro-portion comprising a trypsin-cleavable moiety, wherein cleavage of the trypsin-cleavable moiety mediates the release of oxycodone, wherein the oxycodone is released. prodrug is Compound KC-8 and (b) a trypsin inhibitor that interacts with trypsin that mediates the enzymatically controlled release of the prodrug oxycodone following ingestion of the composition.
[0119] The modalities include a unit dose comprising a composition, such as a pharmaceutical composition, comprising Compound KC-8, a ketone modified prodrug, and a trypsin inhibitor, wherein Compound KC-8 and trypsin inhibitor are present in the unit dose in an efficient amount to provide a pre-selected pharmacokinetic profile (FC) following ingestion. In additional embodiments, the preselected FC profile comprises at least one FC parameter value which is less than the FC parameter value of oxycodone released after ingesting an equivalent dosage of Compound KC-8 in the absence of the inhibitor. In additional modalities, the value of the FC parameter is selected from an oxycodone Cmax value, an oxycodone exposure value, and a value (oxycodone 1 / Tmax).
[0120] In certain modalities, the unit dose provides a pre-selected FC profile after ingesting at least two unit doses. In related modalities, the preselected FC profile of such unit doses is modified in relation to the FC profile after ingestion of an equivalent dosage of Compound KC-8 without inhibitor. In related modalities, this unit dose provides that the intake of an increasing number of unit doses provides a linear FC profile. In related modalities, this unit dose provides that the intake of an increasing number of unit doses provides a non-linear FC profile. In related modalities, the FC parameter value of the FC profile of such unit dose is selected in an oxycodone Cmax value, an oxycodone value (1 / Tmax), and an oxycodone exposure value.
[0121] The modalities include methods for treating a patient comprising administering any of the compositions, such as pharmaceutical compositions, comprising Compound KC-8 and a trypsin inhibitor or dose units described herein to a patient in need thereof. The modalities include methods for reducing the side effects of therapy comprising administering any of such compositions, for example, pharmaceutical compositions, or dose units described herein to a patient in need thereof. The modalities include methods for improving patient compliance with therapy prescribed by a clinician comprising directing the administration of any such compositions, for example, pharmaceutical compositions, or dose units described herein to a patient in need thereof. These modalities can provide improved patient compliance with a prescribed therapy, compared to a patient's agreement with a prescribed therapy using drug and / or using prodrug without inhibitor compared to prodrug with inhibitor.
[0122] The modalities include methods of reducing the risk of involuntary overdosage of oxycodone comprising directing the administration of any of these compositions, for example, pharmaceutical compositions, or dose units described in this document to a patient in need of treatment.
[0123] The modalities include methods of making a unit dose comprising combining Compound KC-8 and a trypsin inhibitor into a unit dose, wherein Compound KC-8 and trypsin inhibitor are present in the unit dose in an amount effective to attenuate the release of oxycodone from Compound KC-8.
[0124] The modalities include methods of misuse or abuse of multiple dose units of Compound KC-8 comprising combining Compound KC-8 and a trypsin inhibitor into a unit dose, wherein Compound KC-8 and trypsin inhibitor are present in the unit dose in an amount efficient to attenuate the release of oxycodone from Compound KC-8 in such a way that the ingestion of multiple dose units by a patient does not provide a proportional release of oxycodone. In other embodiments, drug release is decreased compared to drug release by an equivalent dosage of prodrug in the absence of inhibitor.
[0125] One embodiment is a method for identifying a trypsin inhibitor and the suitable prodrug Compound KC-8 for formulation in a unit dose. This method can be conducted as, for example, an in vitro assay, an in vivo assay, or an ex vivo assay.
[0126] The modalities include methods for identifying a trypsin inhibitor and the suitable prodrug Compound KC-8 for formulation in a unit dose comprising combining the prodrug Compound KC-8, a trypsin inhibitor, and trypsin in a reaction mixture, and detecting conversion of prodrug, in which a decrease in prodrug conversion in the presence of trypsin inhibitor compared to the conversion of prodrug in the absence of trypsin inhibitor indicates that trypsin inhibitor and KC-8 prodrug Compound are suitable for formulation in a unit dose.
[0127] The modalities include methods for identifying a trypsin inhibitor and the suitable prodrug Compound KC-8 for formulation in a unit dose comprising administering to a animal a trypsin inhibitor and the prodrug Compound KC-8 and detecting the conversion of the prodrug, wherein a decrease in the conversion of oxycodone in the presence of the trypsin inhibitor compared to the conversion of oxycodone in the absence of the trypsin inhibitor indicates that the trypsin inhibitor and the prodrug Compound KC-8 are suitable for formulation in a unit dose. In certain embodiments, administration comprises administering to the animal increasing doses of coded inhibitor with a fixed dose of prodrug. Detection of prodrug conversion can facilitate the identification of the inhibitor dose and the prodrug dose that provide a pre-selected pharmacokinetic (FC) profile. These methods can be conducted as, for example, an in vivo test or an ex vivo test.
[0128] The modalities include methods for identifying a trypsin inhibitor and the suitable prodrug Compound KC-8 for formulation in a unit dose comprising administering a trypsin inhibitor and the pro-drug Compound KC-8 to an animal tissue and detecting the conversion of the prodrug in that a decrease in the conversion of the prodrug in the presence of the trypsin inhibitor compared to the conversion of the prodrug in the absence of the trypsin inhibitor indicates that the trypsin inhibitor and the KC-8 prodrug Compound are suitable for formulation in a unit dose.
[0129] Dosage units of KC-8 Prodrug Compound and Trypsin Inhibitor Having a Desired Pharmacokinetic Profile
[0130] The present disclosure provides unit doses of prodrug and inhibitor that can provide a desired pharmacokinetic (FC) profile. Unit doses can provide a modified FC profile compared to a reference FC profile, as disclosed here. It will be appreciated that a modified FC profile can provide a modified pharmacodynamic (FD) profile. Ingestion of multiples of this unit dose may also provide a desired FC profile.
[0131] Unless specifically indicated otherwise, "unit dose" as used herein refers to a combination of a trypsin cleavable prodrug and a trypsin inhibitor. The "single unit dose" is a single unit of a combination of a trypsin cleavable prodrug and a trypsin inhibitor, wherein the single unit dose provides a therapeutically effective amount of drug (i.e., a sufficient amount of drug to produce a therapeutic effect, for example, a dose within the respective therapeutic window of the drug, or therapeutic range). "Multiple unit doses" or "multiples of a unit dose" or "multiple of a unit dose" refers to at least two single unit doses.
[0132] As used herein, an "FC profile" refers to a drug concentration profile in blood or plasma. This profile can consist of a drug concentration ratio over time (ie, a "concentration-time FC profile") or a drug concentration ratio versus number of doses ingested (ie, a "dose concentration FC profile") ). An FC profile is characterized by FC parameters.
[0133] As used herein, an "FC parameter" refers to a measurement of drug concentration in blood or plasma, such as: 1) "Drug Cmax", the maximum drug concentration achieved in blood or plasma; 2) "Drug Tmax", the time that elapsed after ingestion until Cmax is reached; and 3) "drug exposure" means the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a drug release time course at over a selected period of time (t). The modification of one or more FC parameters provides a modified FC profile.
[0134] For purposes of describing the characteristics of the dose units of the present disclosure, "The FC parameter values" that define an FC profile include drug Cmax (eg, oxycodone Cmax), total drug exposure (eg, area under the curve) (for example, exposure to oxycodone) and 1 / (drug Tmax) (so that a decrease of 1 / Tmax is indicative of a delay in Tmax relative to a reference Tmax) (for example, 1 / Oxycodone Tmax). Thus, a decrease in an FC parameter value relative to a reference FC parameter value can indicate, for example, a decrease in drug Cmax, a decrease in drug exposure and / or a delayed Tmax.
[0135] The unit doses of the present disclosure can be adapted to provide a modified FC profile, for example, an FC profile that is different from that achieved by dosing a certain dose of prodrug in the absence of inhibitor (ie, without inhibitor) . For example, unit doses may provide at least one of decreased drug Cmax, delayed drug Tmax and / or decreased drug exposure compared to taking a dose of the drug in the same amount, but in the absence of an inhibitor. This modification is due to the inclusion of an inhibitor in the unit dose.
[0136] As used here, a "pharmacodynamic profile (FD)" refers to a profile of the efficacy of a drug in a patient (or subject or user), which is characterized by FD parameters. "FD parameters" include "Drug Emax" (maximum drug efficacy), "Drug EC50" (50% Emax drug concentration) and side effects.
[0137] Figure 1 is a schematic graph illustrating an example of the effect of increasing inhibitor concentrations on the drug parameter FC Cmax for a fixed dose of prodrug. At low inhibitor concentrations there may be no detectable effect on drug release, as illustrated by the level portion of the drug Cmax graph (Y axis) versus inhibitor concentration (X axis). As the inhibitor concentration increases, a concentration is reached to which the release of drug from the prodrug is attenuated, causing a decrease or suppression of drug Cmax. Thus, the effect of the inhibitor on a FC parameter of the prodrug for a unit dose of the present disclosure can vary from undetectable, to moderate, to complete inhibition (that is, without detectable drug release).
[0138] A unit dose can be adapted to provide a desired FC profile (for example, a concentration-time FC profile) after ingestion of a single dose. A unit dose can be adapted to provide a desired FC profile (for example, a concentration-dose FC profile) after ingesting multiple unit doses (for example, at least 2, at least 3, at least 4 or more unit doses). Unit doses providing modified FC profiles
[0139] A combination of a prodrug and an inhibitor in a unit dose can provide a desired (or "preselected") FC profile (for example, a concentration-time FC profile) after ingestion of a single dose. The FC profile of this unit dose can be characterized by one or more of a pre-selected drug Cmax, a pre-selected drug Tmax or a pre-selected drug exposure. The FC profile of the unit dose can be modified compared to an FC profile achieved by means of the equivalent dosage of prodrug in the absence of inhibitor (i.e., a dose that is equal to the unit dose with the exception of being devoid of inhibitor).
[0140] A modified FC profile may have a decreased FC parameter value compared to a reference FC parameter value (for example, an FC parameter value of an FC profile after ingestion of a prodrug dosage that is equivalent to a unit dose with the exception of having no inhibitor). For example, a unit dose can provide a decreased drug Cmax, decreased drug exposure and / or delayed drug Tmax.
[0141] Figure 2 shows schematic graphs showing examples of modified FC concentration-time profiles of a single unit dose. Panel A is a schematic graph of the drug concentration in blood or plasma (Y-axis) following a period of time (X-axis) after ingestion of the drug in the absence or in the presence of an inhibitor. The top continuous line in Panel A provides an example of drug concentration after ingestion of the drug without inhibitor. The lower dashed line in Panel A represents the drug concentration after ingestion of the same dose of prodrug with inhibitor. Ingestion of inhibitor with prodrug provides a decreased drug Cmax relative to drug Cmax resulting from ingesting the same amount of prodrug in the absence of inhibitor. Panel A also illustrates that the total drug exposure after ingesting a drug with an inhibitor is also decreased relative to ingesting the same amount of a drug without an inhibitor.
[0142] Panel B of Figure 2 provides another example of a unit dose having a modified FC concentration-time profile. As in Panel A, the top continuous line represents the drug concentration over time in the blood or plasma after ingesting the drug without inhibitor, while the dotted bottom line represents the drug concentration after ingesting the same amount of drug. prodrug with inhibitor. In this example, the unit dose provides an FC profile having a decreased drug Cmax, a decreased drug exposure and a delayed drug Tmax (i.e., (1 / drug Tmax) decreased) relative to ingestion of the same dose of drug without inhibitor.
[0143] Panel C of Figure 2 provides another example of a unit dose having a modified FC concentration-time profile. As in Panel A, the solid line represents the drug concentration over time in blood or plasma after ingesting the drug without inhibitor, whereas the dashed line represents the drug concentration after ingesting the same amount of the drug with inhibitor. In this example, the unit dose provides an FC profile having a delayed drug Tmax (i.e., 1 / decreased drug Tmax) relative to ingestion of the same dose of prodrug without inhibitor.
[0144] Unit doses that provide a modified FC profile (for example, a decreased drug Cmax and / or delayed drug Tmax compared to an FC drug profile or an FC drug profile without inhibitor) have application in adjusting the drug dose of according to a patient's needs (for example, by selecting a particular unit dose and / or selecting a dosage regimen), reducing side effects and / or improving patient compliance (compared to side effects or agreement associated with drug or prodrug without inhibitor). As used here, "patient agreement" refers to the fact that a patient follows the guidance of a clinician (for example, a doctor), including taking a dose that is not significantly higher or significantly lower than prescribed. These unit doses also reduce the risk of misuse, abuse or overdose by a patient compared to the risk (s) associated with a drug or prodrug without an inhibitor. For example, unit doses with a decreased drug Cmax provide less reward for ingestion than a dose of the same amount of drug and / or the same amount of prodrug without inhibitor. Unit doses providing modified FC profiles by ingesting multiple unit doses
[0145] A unit dose of the present disclosure can be adapted to provide a desired FC profile (for example, a concentration-time FC profile or concentration-dose FC profile) after ingesting multiples of a unit dose (for example, at least 2, at least 3, at least 4 or more unit doses). A concentration-dose FC profile refers to the relationship between a selected FC parameter and a number of single unit doses ingested. This profile can be dose-proportional, linear (a linear FC profile) or non-linear (a non-linear FC profile). A modified concentration-dose FC profile can be provided by adjusting the relative amounts of prodrug and inhibitor contained in a single unit dose and / or using a different prodrug and / or inhibitor.
[0146] Figure 3 provides schematic graphs of examples of concentration-dose FC profiles (exemplified by drug Cmax, Y-axis) that can be provided by ingesting multiples of a unit dose (X-axis) of the present disclosure. Each profile can be compared with a concentration-dose FC profile provided by increasing doses of drug alone, in which the amount of drug, in blood or plasma, in one dose represents an therapeutically effective amount equivalent to the amount of drug released in blood or plasma by a unit dose of disclosure. This "drug alone" FC profile is typically dose-proportional, having a positive linear slope at an angle of forty-five degrees. It should also be appreciated that a concentration-dose FC profile resulting from ingesting multiples of a unit dose of the disclosure can also be compared with other references, such as a concentration-dose FC profile provided by ingesting an increasing number of doses of prodrug without inhibitor. , wherein the amount of drug released into the blood or plasma by a single dose of prodrug in the absence of inhibitor represents an therapeutically effective amount equivalent to the amount of drug released into the blood or plasma by a unit dose of the disclosure.
[0147] As illustrated by the relationship between the concentration of prodrug and inhibitor in Figure 1, a unit dose may include inhibitor in an amount that does not detectably affect drug release after ingestion. The ingestion of multiples of this unit dose can provide an FC concentration-dose profile such that the relationship between the number of unit doses ingested and the FC parameter value is linear with a positive slope, which is similar, for example, to an FC profile proportional to the dose of increasing amounts of prodrug alone. Panel A in Figure 3 illustrates one of these profiles. Unit doses that provide a concentration-dose FC profile having this undetectable change in drug Cmax in vivo, compared to the drug profile alone, may have application in preventing enzyme conversion of the drug from a unit dose that has sufficient inhibitor to reduce or prevent in vitro cleavage of the enzymatically cleavable prodrug by its respective enzyme.
[0148] Panel B in Figure 3 represents a concentration-dose FC profile such that the relationship between the number of unit doses ingested and an FC parameter value is linear with a positive slope, where the profile exhibits a reduced slope relative to panel A. unit dose provides a profile with an FC parameter value (for example, drug Cmax) decreased relative to a reference FC parameter value showing dose proportionality.
[0149] The dose-concentration FC profiles after ingesting multiples of a unit dose may be non-linear. Panel C in Figure 3 represents an example of a non-linear, two-phase concentration-dose FC profile. In this example, the biphasic FC concentration-dose profile contains a first phase along which the FC concentration-dose profile has a positive rise, and then a second phase along which the relationship between the number of unit doses ingested and a value parameter FC (for example, drug Cmax) is relatively flat (substantially linear with zero slope). For that unit dose, for example, drug Cmax can be increased to a selected number of unit doses (for example, 2, 3 or 4 unit doses). However, intake of additional unit doses does not provide a significant increase in drug Cmax.
[0150] Panel D in Figure 3 represents another example of a non-linear, two-phase concentration-dose FC profile. In this example, the biphasic FC concentration-dose profile is characterized by a first phase along which the FC concentration-dose profile has a positive rise, and a second phase along which the relationship between the number of unit doses ingested and a FC parameter value (for example, drug Cmax) decreases. Unit doses that provide this concentration-dose FC profile provide an increase in drug Cmax for a selected number of unit doses (for example, 2, 3 or 4 unit doses) ingested. However, ingesting more additional unit doses does not provide a significant increase in drug Cmax and, instead, provides decreased drug Cmax.
[0151] Panel E in Figure 3 represents a concentration-dose FC profile in which the relationship between the number of unit doses ingested and an FC parameter (for example, drug Cmax) is linear with zero slope. These unit doses do not provide a significant increase or decrease in drug Cmax with the ingestion of multiples of unit doses.
[0152] Panel F in Figure 3 represents an FC concentration-dose profile in which the relationship between the number of unit doses ingested and an FC parameter value (for example, drug Cmax) is linear with a negative slope. Thus, drug Cmax decreases as the number of unit doses ingested increases.
[0153] Unit doses that provide FC concentration-dose profiles when multiples of a unit dose are ingested have application in adjusting a dosage regimen to provide a therapeutic level of drug released while reducing the risk of overdose use. misuse or abuse. This risk reduction can be compared with a reference, for example, with the administration of drug alone or prodrug alone. In one embodiment, the risk is reduced compared to the administration of a drug or prodrug that provides a proportional dose-concentration FC profile. A unit dose that provides a concentration-dose FC profile can reduce the risk of overdosing by a patient through inadvertent ingestion of unit doses above a prescribed dosage. This unit dose can reduce the risk of misuse by a patient (for example, through self-medication). This unit dose can discourage abuse by deliberately ingesting multiple unit doses. For example, a unit dose that provides a biphasic dose-concentration FC profile may allow an increase in drug release for a limited number of ingested unit doses, after an increase in drug release with the ingestion of more unit doses is not achieved. . In another example, a unit dose that provides a zero-tilt concentration-dose FC profile may allow the retention of a similar drug release profile regardless of the number of unit doses ingested.
[0154] The ingestion of multiples of a unit dose can provide an adjustment of an FC parameter value relative to the ingestion of multiples of the same dose (as a drug alone or as a prodrug) in the absence of inhibitor, so that, for example, the ingestion of a selected number (eg 2, 3, 4 or more) of a single unit dose provides a decrease in an FC parameter value compared to ingesting the same number of doses in the absence of inhibitor.
[0155] Pharmaceutical compositions include those that have an inhibitor to provide protection of a therapeutic compound against degradation in the Gl tract. The inhibitor can be combined with a drug (i.e., not a prodrug) to provide protection of the drug against degradation in the Gl system. In this example , the inhibitor and drug compositions provide a modified FC profile by increasing an FC parameter. The inhibitor can also be combined with a prodrug that is susceptible to degradation by a Gl enzyme and has an action site outside the Gl tract. In this composition, the inhibitor protects the ingested prodrug in the Gl tract before its distribution outside the Gl tract and divage at a desired site of action. Methods used to define relative amounts of prodrug and inhibitor in a unit dose.
[0156] Unit doses that provide a desired FC profile, such as a desired concentration-time FC profile and / or a desired concentration-dose FC profile, can be prepared by combining a prodrug and an inhibitor in a unit dose in relative amounts effective to provide drug release. which provides a desired drug profile FC after ingestion by a patient.
[0157] Prodrugs can be selected as suitable for use in a unit dose by determining the trypsin-mediated drug release competence of the prodrug. This can be achieved in vitro, in vivo or ex vivo.
[0158] In vitro assays can be conducted by combining a prodrug with trypsin in a reaction mixture. Trypsin can be provided in the reaction mixture in an amount sufficient to catalyze the breakdown of the prodrug. The tests are conducted under suitable conditions and, optionally, in conditions that mimic those found in a G tract! of a subject, for example, human. "Prodrug conversion" refers to the release of drug from the prodrug. Prodrug conversion can be assessed by detecting the level of a prodrug conversion product (e.g., released drug) and / or detecting a level of prodrug that is maintained in the presence of trypsin. The conversion of the prodrug can also be assessed by detecting the rate at which a product of the conversion of the prodrug occurs or the rate at which the prodrug disappears. An increase in released drug, or a decrease in prodrug, indicates that conversion of the prodrug has occurred. Prodrugs that exhibit an acceptable level of prodrug conversion in the presence of trypsin over an acceptable period of time are suitable for use in a unit dose in combination with a trypsin inhibitor.
[0159] In vivo tests can assess the suitability of a prodrug for use in a unit dose by administering the prodrug to an animal (for example, a human or a non-human animal, for example, rat, dog, pig, etc.). This administration can be enteral (for example, oral administration). The conversion of the prodrug can be detected, for example, by detecting a product of the conversion of the prodrug (for example, released drug or a released drug metabolite) or detecting the prodrug in the animal's blood or plasma in an instant (s) desired (s) after administration.
[0160] Ex vivo assays, such as the visceral loop or inverted visceral loop assay, can assess the suitability of a prodrug for use in a unit dose, for example, by administering the prodrug to a connected section of an animal's intestine. The conversion of the prodrug can be detected, for example, by detecting a product of the conversion of the prodrug (for example, released drug or a released drug metabolite) or detecting the prodrug in the visceral loop attached to the animal in an instant (s) desired (s) after administration.
[0161] Inhibitors are generally selected based on, for example, activity in the interaction with trypsin that mediates the release of drug from the prodrug with which the inhibitor is to be coded. These tests can be conducted in the presence of an enzyme with or without a prodrug. Inhibitors can also be selected according to properties such as half-life in the Gl system, potency, avidity, affinity, molecular size and / or enzyme inhibition profile (for example, degree of slope of the inhibition curve in an enzyme activity assay, inhibition initiation rate). Inhibitors for use in prodrug-inhibitor combinations can be selected using in vitro, in vivo and / or ex vivo assays.
[0162] One embodiment is a method for identifying a prodrug and trypsin inhibitor suitable for formulation in a unit dose where the method comprises combining a prodrug (eg, Compound KC-8), a trypsin inhibitor, and trypsin in a mixture reaction and detect the conversion of prodrug. This combination is tested for an interaction between the prodrug, inhibitor and enzyme, that is, tested to determine how the inhibitor will interact with the enzyme that mediates the enzymatically controlled release of the drug from the prodrug. In one embodiment, a decrease in the conversion of the prodrug in the presence of the trypsin inhibitor compared to the conversion of the prodrug in the absence of the trypsin inhibitor indicates that the prodrug and trypsin inhibitor are suitable for formulation in a unit dose. This method may consist of an in vitro assay.
[0163] One embodiment is a method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a unit dose where the method comprises administering to a animal a prodrug (for example, Compound KC-8) and a trypsin inhibitor and detecting the trypsin. prodrug conversion. In one embodiment, a decrease in prodrug conversion in the presence of the trypsin inhibitor compared to the conversion of the prodrug in the absence of the trypsin inhibitor indicates that the prodrug and trypsin inhibitor are suitable for formulation in a unit dose. Such a method can be an in vivo test; for example, the prodrug and trypsin inhibitor can be administered orally. Such a method can also be an ex vivo test; for example, the prodrug and trypsin inhibitor can be administered orally or to a tissue, such as the intestine, which is at least temporarily exposed. Detection can occur in blood or plasma or tissue. As used here, fabric refers to the fabric itself and can also refer to the content within the fabric.
[0164] One embodiment is a method for identifying a prodrug and a trypsin inhibitor suitable for formulation in a unit dose in which the method comprises administering a prodrug and a trypsin inhibitor to an animal tissue that has been removed from an animal and detecting the conversion of the prodrug. . In one embodiment, a decrease in the conversion of the prodrug in the presence of the trypsin inhibitor compared to the conversion of the prodrug in the absence of the trypsin inhibitor indicates that the prodrug and trypsin inhibitor are suitable for formulation in a unit dose.
[0165] In vitro assays can be conducted by combining a prodrug, a trypsin inhibitor and trypsin in a reaction mixture. Trypsin may be provided in the reaction mixture in an amount sufficient to catalyze cleavage of the prodrug, and assays conducted under suitable conditions, optionally under conditions that mimic those found in the GI tract of a subject, for example, human. The conversion of the prodrug can be assessed by detecting a level of a prodrug conversion product (e.g., the released drug) and / or detecting the level of prodrug maintained in the presence of trypsin. The conversion of the prodrug can also be assessed by detecting the rate at which a product of the conversion of the prodrug occurs or the rate at which the prodrug disappears. The conversion of the prodrug that is modified in the presence of inhibitor, compared to a level of conversion of the prodrug in the absence of inhibitor, indicates that the inhibitor is suitable for attenuating the conversion of the prodrug and for use in a unit dose. Reaction mixtures having a fixed amount of prodrug and increasing amounts of inhibitor, or a fixed amount of inhibitor and increasing amounts of prodrug, can be used to identify relative amounts of prodrug and inhibitor that provide a desired modification of the prodrug conversion.
[0166] In vivo assays can evaluate combinations of prodrugs and inhibitors by coding the prodrug and inhibitor to an animal. This coding can be enteral. "Codosing" refers to the administration of prodrug and inhibitor in the form of separate doses or a combined dose (i.e., in the same formulation). The conversion of the prodrug can be detected, for example, through the detection of a product of the conversion of the prodrug (for example, released drug or drug metabolite) or detection of the prodrug in the animal's blood or plasma at the desired time (s) ( s) after administration. Combinations of prodrug and inhibitor that provide provide a level of conversion of the prodrug that gives rise to a desired FC profile, compared, for example, with prodrug without inhibitor.
[0167] Combinations of relative amounts of prodrug and inhibitor can be identified that provide a desired FC profile by dosing animals with a fixed amount of prodrug and increasing amounts of inhibitor, or with a fixed amount of inhibitor and increasing amounts of prodrug. One or more FC parameters can then be evaluated, for example, drug Cmax, drug Tmax and drug exposure. Relative amounts of prodrug and inhibitor that provide a desired FC profile are identified as amounts of prodrug and inhibitor for use in a unit dose. The FC profile of the combination of prodrug and inhibitor can be characterized, for example, by a decreased parameter value FC compared to the prodrug without inhibitor. A decrease in the FC parameter value of an inhibitor-prodrug combination (for example, a decrease in drug Cmax, a decrease in drug 1 / Tmax (i.e., a delay in drug Tmax) or a decrease in drug exposure ) with respect to a corresponding FC parameter value after administration of prodrug without inhibitor can be an indicator of an inhibitor-prodrug combination that can provide a desired FC profile. The assays can be conducted with different relative amounts of inhibitor and prodrug.
[0168] In vivo assays can be used to identify combinations of prodrug and inhibitor that provide unit doses that provide a desired concentration-dose FC profile after ingesting multiples of the unit dose (for example, at least 2, at least 3, at least 4 or more ). Ex vivo assays may be conducted by direct administration of prodrug and inhibitor to a tissue, and / or its contents, from an animal, such as the intestine, including by introduction into the lumen of a connected intestine (for example, an assay). visceral loop, or intestinal loop, or an inverted visceral loop assay). An ex vivo assay can also be conducted by excising a tissue and / or its contents from an animal and introducing a prodrug and inhibitor into those tissues and / or contents.
[0169] For example, a dose of prodrug is selected that is desired for a single unit dose (for example, an amount that provides an effective level of drug in the plasma). Then a multiple of unit doses is selected for which it is intended to test a relationship between that multiple and an FC parameter. For example, if it is intended to design a concentration-dose FC profile for ingestion of 2, 3, 4, 5, 6, 7, 8, 9 or 10 unit doses, then the amount of prodrug equivalent to the ingestion of that same number of doses is determined. unit doses (referred to as "high dose"). The multiple of unit doses can be selected based on the number of pills taken for which drug Cmax is modified relative to the intake of the single unit dose. For example, if the profile is intended to prevent abuse, then a multiple of 10 can be selected, for example, a variety of different inhibitors (for example, from a panel of inhibitors) can be tested using different relative amounts. inhibitor and prodrug. Assays can be used to identify the appropriate combination (combinations) of inhibitor and prodrug in order to obtain a single unit dose that is therapeutically effective, where that combination, when ingested as a multiple of unit doses, provides a parameter Modified FC compared to ingesting the same multiple of drug or prodrug alone (where a single dose of drug or prodrug alone releases the same amount of drug in blood or plasma that is released by a single unit dose).
[0170] Increasing amounts of inhibitor are then coded in animals with the high dose of the prodrug. The level of inhibitor dose that provides a desired drug Cmax is identified after ingestion of the high dose of the drug, and the resulting inhibitor-drug ratio is determined.
[0171] Prodrug and inhibitor are then coded in amounts equivalent to the inhibitor-prodrug ratio that provided the desired result at the high dose of prodrug. Then, the value of the FC parameter of interest (for example, drug Cmax) is evaluated. If a desired FC parameter value results after ingesting the equivalent of the single unit dose, then single unit doses are identified that provide a desired concentration-dose FC profile. For example, when a linear zero dose profile is desired, the drug Cmax after ingestion of a single unit dose does not increase significantly after ingestion of a multiple number of the single unit doses. Methods of manufacture, formulation and packaging of unit doses
[0172] The unit doses of the present disclosure can be prepared using manufacturing methods available in the art and can take a variety of forms suitable for enteral administration (including oral, buccal and sublingual), for example, in the form of a tablet, capsule, thin film, powder, suspension, solution, syrup, dispersion or emulsion. The unit dose may contain conventional components in pharmaceutical preparations, for example, one or more carriers, binders, lubricants, excipients (for example, to provide controlled release characteristics), pH modifiers, flavoring agents (for example, sweeteners), agents volume, coloring agents or other active agents. Unit doses of the present disclosure may include an enteric coating or other component (s) to facilitate protection against stomach acid, when desired.
[0173] Unit doses can be of any suitable size or shape. The unit dose can have any form suitable for enteral administration, for example, ellipsoid, lenticular, circular, rectangular, cylindrical and the like.
[0174] The unit doses provided in the form of dry unit doses can have a total weight from about 1 microgram to about 1 gram, and can range from about 5 micrograms to 1.5 grams, from about 50 micrograms to 1 gram, from about 100 micrograms to 1 gram, from 50 micrograms to 750 milligrams, and can range from about 1 microgram to 2 grams.
[0175] Unit doses can comprise components in any relative amounts. For example, unit doses can be from about 0.1% to 99% by weight of active ingredients (ie prodrug and inhibitor) by total weight of the unit dose (0 , 1% to 99% of the combined total weight of prodrug and inhibitor per total weight of the single unit dose). In some embodiments, the unit doses can be from 10% to 50%, from 20% to 40%, or about 30% by weight of active ingredients per total weight of the unit dose.
[0176] Unit doses can be provided in a variety of different ways, and can optionally be provided in a manner suitable for storage. For example, unit doses can be arranged in a container suitable for containing a pharmaceutical composition. The container can be, for example, a bottle (for example, with a closure device, such as a lid), a blister pack (for example, which can provide for the closure of one or more unit doses per well), a vial, flexible packaging (for example, Mylar bags or plastic bags), an ampoule (for single unit doses in solution), a dropper, thin film, a tube and the like.
[0177] The containers may include a lid (for example, screw cap) that is removably connected to the container in an opening through which the unit doses arranged within the container can be accessed.
[0178] Containers may include a seal that can serve as a tamper-proof and / or tamper-proof element, the seal of which is destroyed by access to a unit dose disposed within the container. Such sealing elements may consist, for example, of a frangible element that is broken or otherwise modified by access to a unit dose disposed within the container. Examples of such frangible sealing elements include a seal positioned over the opening of a container so that access to a unit dose contained in the container requires destruction of the seal (for example, by peeling and / or perforating the seal). Examples of frangible sealing elements include a frangible ring arranged around the opening of a container and connected to a lid, so that the ring is destroyed by opening the lid to access the unit doses contained in the container.
[0179] Dry and liquid unit doses can be placed in a container (for example, bottle or packaging, for example, a flexible bag) with a size and configuration adapted to maintain the stability of unit doses over a period of time during which unit doses are distributed in a prescription. For example, containers can be sized and configured to contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more single dry or liquid unit doses. Containers can be sealed or resealable. Containers can be packaged in a package (for example, for shipping from a manufacturer to a pharmacy or other distribution center). These packages can be boxes, tubes, or have another configuration, and can be made of any material (for example, cardboard, plastic and the like). The packaging system and / or containers disposed there may have one or more labels affixed (for example, to provide information such as the batch number, type of unit doses, manufacturer and the like).
[0180] The container may include a moisture barrier and / or light barrier, for example, to facilitate maintaining the stability of the active ingredients in the unit doses contained therein. When the unit dose is a dry unit dose, the container can include a desiccant unit that is disposed within the container. The container can be adapted to contain a single unit dose or multiples of a unit dose. The container may include a delivery control mechanism, such as a closing mechanism, which facilitates the maintenance of the dosing regimen.
[0181] The unit doses can be provided in solid or se-missolide form, and can consist of a dry unit dose. "Dry unit dose" refers to a unit dose that is different from a unit dose that is in completely liquid form. Examples of dry unit doses include, for example, tablets, capsules (e.g., solid capsules, capsules containing liquid), thin film, microparticles, granules, powder and the like. Unit doses can be provided in the form of liquid unit doses, where unit doses can be provided in the form of a single or multiple doses of a formulation containing prodrug and inhibitor in liquid form. Single doses of a dry or liquid unit dose can be arranged within a sealed container, and sealed containers are optionally provided in a packaging system, for example, to provide a prescribed number of doses, to provide the dispatch of unit doses and the like .
[0182] Unit doses can be formulated so that the prodrug and inhibitor are present in the same carrier, for example, solubilized or suspended in the same matrix. Alternatively, the unit doses can be composed of two or more portions, in which the prodrug and inhibitor can be provided in the same portion or in different portions, and can be provided in adjacent or non-adjacent portions.
[0183] Unit doses can be provided in a container in which they are arranged, and can be provided as part of a packaging system (optionally with instructions for use). For example, unit doses containing different amounts of prodrug can be provided in separate containers, the containers of which can be arranged in a larger container (for example, to facilitate protection of unit doses for shipping). For example, one or more unit doses, as described herein, can be provided in separate containers, where unit doses of different composition are provided in separate containers, and the separate containers are arranged in a package for distribution.
[0184] In another example, unit doses can be provided in a dual-chamber dispenser, where a first chamber contains a prodrug formulation and a second chamber contains an inhibitor formulation. The dispenser can be adapted to provide a mixture of a prodrug formulation and an inhibitor formulation prior to ingestion. For example, the two chambers of the dispenser may be separated by a removable wall (e.g., frangible wall) that is broken or removed prior to administration, to allow mixing of the formulations of the two chambers. The first and second chambers can terminate in a distribution discharge port, optionally via a common chamber. The formulations can be provided in dry or liquid form, or a combination of these. For example, the formulation in the first chamber can be liquid and the formulation in the second chamber can be dried, both can be dried, or both can be liquid.
[0185] Unit doses that provide controlled release of prodrug, inhibitor, or prodrug and inhibitor are contemplated by the present disclosure, where "controlled release" refers to the release of one or both of the prodrug and inhibitor from the unit dose over a selected period of time and / or in a pre-selected mode. Methods of using unit doses
[0186] Unit doses are advantageous because they can be used in methods to reduce side effects and / or improve drug tolerability of patients in need, for example, by limiting an FC parameter as disclosed here. Thus, the present disclosure provides methods for reducing side effects by administering a unit dose of the present disclosure to a needy patient, in order to provide a reduction in side effects compared to those associated with drug administration and / or compared to administration of prodrug without inhibitor. The present disclosure also provides methods for improving the tolerability of drugs by administering a unit dose of the present disclosure to a needy patient, in order to provide improved tolerability compared to drug administration and / or compared to administration of prodrug without inhibitor.
[0187] Unit doses can be used in methods to increase a patient's compliance with a therapy prescribed by a clinician, where these methods involve the direct administration of a unit dose described here to a patient in need of therapy, in order to provide increased patient compliance. patient compared to therapy involving drug administration and / or compared to drug administration without inhibitor. These methods can help to increase the likelihood that a therapy specified by a clinician will occur as prescribed.
[0188] Unit doses can provide increased patient compliance and control by the clinician. For example, by limiting an FC parameter (for example, as drug Cmax or drug exposure) when multiple (eg, two or more, three or more, or four or more) unit doses are ingested, a patient requiring a higher dose of drug should seek the assistance of a clinician. Unit doses can provide control of the degree to which a patient can easily "self-medicate", and can additionally provide the patient to adjust the dose to a dose within a permissible range. Unit doses can provide reduced side effects, for example, by providing drug distribution at an effective dose, but with a modified FC profile over a treatment period, for example, as defined by a decreased FC parameter (for example, Decreased drug Cmax, decreased drug exposure).
[0189] Unit doses can be used in methods to reduce the risk of accidental overdose of drugs that may follow the ingestion of multiple doses taken at the same time or over a short period of time. These methods of the present disclosure may provide a reduction in the risk of accidental overdose use, compared to the risk of accidental overdose use and / or in comparison with the risk of accidental overdose use of a drug without inhibitor. These methods involve the direct administration of a dosage described here to a patient in need of drug release by conversion of the prodrug. These methods can help prevent accidental overdose due to the unit dose being misused, intentionally or accidentally.
[0190] The present disclosure provides methods to reduce the misuse and abuse of a drug, as well as to reduce the risk of overdose use, which can accompany the ingestion of multiple doses of a drug, for example, taken at the same time. These methods usually involve combining a unit dose of a prodrug and a trypsin inhibitor that mediates the drug release from the prodrug, where the inhibitor is present in the unit dose in an amount effective to attenuate the release of the drug from the prodrug, for example, after ingesting multiple dose units per patient. These methods provide a modified concentration-dose FC profile while providing therapeutically effective levels from a single unit dose, as directed by the clinician prescribing the treatment. These methods can provide, for example, risk reduction that can accompany the misuse and / or abuse of a drug, in particular when the conversion of the drug provides release of a narcotic or other drugs (for example, opioid). For example, when the prodrug provides the release of a drug, unit doses may provide a reduction in the reward that can follow the ingestion of multiples of unit doses of a drug.
[0191] Unit doses can provide clinicians with greater flexibility in prescribing a drug. For example, a clinician may prescribe a dosage regimen involving different dose strengths, which may involve two or more different unit doses of prodrug and inhibitor with different relative amounts of prodrug, different amounts of inhibitor, or different amounts of prodrug and inhibitor. These unit doses with different potencies can provide drug distribution according to different FC parameters (for example, drug exposure, drug Cmax and the like, as described here). For example, a first unit dose can provide delivery of a first dose of drug after ingestion, and a second unit dose can provide delivery of a second dose of drug after ingestion. The first and second doses of prodrug of the unit doses may have different potencies, for example, the second dose may be greater than the first dose. Thus, a clinician can prescribe a collection of two or more, or three or more unit doses of different potencies, which can be accompanied by instructions to facilitate a degree of self-medication, for example, to increase the distribution of an opioid drug according to a patient's needs for pain management. Counteract trypsin-mediated release of oxycodone from the prodrug
[0192] The disclosure provides a composition comprising Compound KC-8 and a trypsin inhibitor that reduces the potential abuse of the drug. A trypsin inhibitor can counteract a user's ability to apply trypsin to produce the oxycodone release of the ketone-modified oxycodone prodrug, Compound KC-8, in vitro. For example, if an abuser attempts to incubate trypsin with a composition of modalities that include Compound KC-8 and a trypsin inhibitor, the trypsin inhibitor can reduce the action of added trypsin, thereby preventing attempts to release oxycodone with the abuse objective. EXAMPLES
[0193] The following examples are presented in order to provide those skilled in the art with a full disclosure and description of how to make and use the modalities, and are not intended to limit the scope of what the inventors consider to be their invention nor are they intended to designate the experiments to follow as being all or just the experiments performed. Efforts have been made to ensure accuracy with respect to the numbers used (for example, quantities, temperature, etc.), but some errors and experimental deviations should be considered. Unless otherwise stated, the parts are parts by weight, the molecular weight is the average molecular weight, the temperature is in degrees Celsius, the pressure is at or about atmospheric. Common abbreviations can be used. Synthesis of Opioid Prodrugs with Modified Ketone Example 1: Synthesis of oxycodone 6- (N-methyl-N- (2-amino) ethylcarbamate (Compound KC-19)
[0194] 2- (Aminoethyl) -methyl-carbamic acid benzyl ester (2.0 g, 9.6 mmols) was dissolved in dichloroethene (DCE) (20 ml) at room temperature. Triethyl amine (NEt3) (1.40 mL, 11.5 mmol) was added, followed by di-tert-butyl dicarbonate (B0C2O) (10.5 g, 48 mmol) and dimethylaminopyridine (DMAP) (120 mg) . The reaction mixture was stirred at room temperature under nitrogen (N2) for 2 h and then heated to 60 ° C for 16 h. The reaction mixture was then concentrated. The residue was purified by chromatography on silica gel, using 4/1 hexanes / EtOAc, to give Compound A a 86% yield (3.4 g, 8.3 mmol). MS: (m / z) calculated: 408.2, observed (M + Na +) 431.9. Preparation of Compound B
[0195] Compound A (1.3 g, 3.18 mmol) was dissolved in methanol / EtOAc (10 mL / 3 mL, respectively). The mixture was deaerated and saturated with N2. Palladium on carbon (Pd / C) (330 mg, 5% on carbon) was added. The mixture was stirred in a Parr hydrogenation flask (344.74 kPa (50 psi H2)) for 4 h. The mixture was then filtered through a pad of celite, and the filtrate was concentrated to give Compound B (1.08 g, the yield exceeded the amount). Compound B was used without further purification. Preparation of Compound C
[0196] Compound B (500 mg, 1.82 mmol) and NEt3 (0.4 mL, 2.74 mmol) were mixed together in dichloromethane (4 mL). The mixture was added to a pre-cooled phosgene solution at 0 ° C (5.5 mL, 0.5 M in toluene). The reaction mixture was stirred at 0 ° C for 1 h, followed by dilution with ether (20 ml) and filtration through a paper filter. The filtrate was concentrated and passed through a small silica gel column (10 cm X 3 cm), and eluted with 3/1 hexanes / EtOAc. The portions were concentrated to give N, N-Bis (tert-butyl) N'-2- (chlorocarbonyl (methyl) amino) ethylcarbamate (Compound C) as a colorless solid in a quantitative yield (615 mg, 1.82 mmol). MS: (m / z) calculated: 336.1, observed (M + Na +) 359.8. Synthesis of Oxycodone 6- (N-methyl-N- (2-amino) ethylcarbamate (Compound KC-19)
[0197] Oxycodone free base (6.5 g, 20.6 mmols) was dissolved dry, deaerated in tetrahydrofuran (120 ml), and the mixture was cooled to -10 ° C using a dry ice / acetone bath. Potassium bis (trimethylsilyl) amide (KHMDS) (103.0 mL, 51.6 mmol, 0.5 M in toluene) was added via cannula. The mixture was stirred under N2 at less than -5 ° C for 30 min. N-2- (chlorocarbonyl (methyl) amino) ethylcarbamate of N, N-Bis (tert-butyl) (8.0 g, 23.7 mmol), (Compound C) in THF (30 mL) was then added via cannula for 15 min. The mixture was stirred at -5 ° C for 30 min. Another portion of chloride and carbamoyl (4.0 g, 11.9 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 hours. Sodium bicarbonate (10 ml, saturated aqueous) was added. The mixture was concentrated in vacuo to half its initial volume. EtOAc (50 ml) was added, and the layers were separated. The organic phase was washed further with water (3 X 20 ml) and sodium chloride saline solution (40 ml), and then concentrated. The residue was purified by chromatography on silica gel, using DCM / MeOH (gradient 100/1 to 100/15), giving rise to a white foam in 55% yield (7.0 g, 13.4 mmols) . This material was dissolved in a 1: 1 mixture of DCM / trifluoroacetic acid (TFA) (20 ml / 20 ml) at room temperature and stirred for 1 h. The solution was then concentrated in vacuo to obtain an oxycodone 6- (N-methyl-N- (2-amino) ethylcarbamate TFA salt (Compound KC-19) as a thick oil (7.3 g, 11.4 mmols, 99% purity) MS: (m / z) calculated: 415.2, observed (M + H +) 416.5.
[0198] Example 2: Synthesis of N-1- [2- (oxycodone-6-enol-carbonyl-methyl-amino) -ethylamine] -malonic arginine (Compound KC-3) [also called: N - {(S) - acid 4-guanidino-1- [2- (methyl - [(5R, 9R, 13S, 14S) -4,5a-epoxy-6,7-didehydro-14-hydroxy-3-methoxy-17-methylmorfinan-6-oxy ] carbonyl-amino) -ethylcarbamoyl] -butyl} -malonic]
[0199] The solution of N-methylethylenediamine (27.0 g, 364 mmols) and ethyl tri-fluoroacetate (96.6 ml, 812 mmols) in a mixture of ACN (350 ml) and water (7.8 ml, 436 mmols) ) was refluxed with agitation overnight. The solvents were evaporated in vacuo. The residue was evaporated again with i-PrOH (3 x 100 ml), followed by crystallization by heating-cooling from DCM (500 ml). The crystals formed were filtered, washed with DCM and dried in vacuo to provide Compound D (88.3 g, 85%) as a white powdery solid. Preparation of Compound E
[0200] A solution of Compound D (88.2 g, 311 mmols) and DIEA (54.1 ml, 311 mmols) in THF (350 ml) was cooled in an ice bath, followed by the addition of a solution of N- (benzyloxycarbonyl) ) succinimide (76.6 g, 307 mmols) in THF (150 ml) dropwise over a period of 20 min. The temperature of the reaction mixture was raised to room temperature and stirring was continued for an additional 30 min. The solvents were then evaporated and the resulting residue was dissolved in EtOAc (600 ml). The organic layer was extracted with 5% NaHCO3 (2 x 150 ml) and sodium chloride saline (150 ml). The organic layer was evaporated to provide Compound E as a yellowish oil. LC-MS [M + H] 305.1 (C13H15F3N2O3 + H, calc: 305.3). Compound E was used directly in the next reaction without purification as a solution in MeOH. Preparation of Compound F
[0201] To a solution of Compound E (~ 311 mmol) in MeOH (1.2 L) was added a solution of LiOH (14.9 g, 622 mmol) in water. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated to 75% of the initial volume, followed by dilution with water (400 ml). The solution was extracted with EtOAc (2 x 300 ml). The organic layer was washed with brine (200 ml), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in ether (300 ml) and treated with 2 N HCI / ether (200 ml). The formed precipitate was filtered, washed with ether and dried in vacuo to provide the hydrochloric salt of Compound F (67.8 g, 89%) as a white solid. LC-MS [M + H] 209.0 (C11H16N2O2 + H, calc: 209.3). Compound F was used directly in the next reaction without purification as a DMF solution. Preparation of Compound G
[0202] The Boc-Arg (Pbf) -OH solution (16.0 g, ~ 30.4 mmols), Compound F hydrochloride (8.2 g, 33.4 mmols), and DIEA (16.9 mL , 97.2 mmols) in DMF (150 ml) was cooled in an ice bath followed by the addition of a solution of HATU (13.8 g, 36.4 mmols) dropwise over 20 min. The temperature of the reaction mixture was raised to room temperature, and stirring was continued for an additional 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (3 x 200 ml) and sodium chloride saline (200 ml). The organic layer was dried over MgSO4 and evaporated to provide Compound G (24.4 g, yield exceeded the amount) as a yellowish oil. LC-MS [M + H] 717.4 (C35H52N6O8S + H, calc: 717.9). Compound G was used directly in the next reaction without purification as a dioxane solution. Preparation of Compound H
[0203] Compound G (24.4 g, ~ 30.4 mmol) was dissolved in dioxane (150 mL) and treated with 4 N HCl / dioxane (150 mL, 600 mmol) at room temperature for 1 h. The solvent was then evaporated. The residue was resuspended in i-PrOH (100 ml), and the mixture was evaporated (the procedure was repeated twice). The residue was then dried in vacuo to provide Compound H (21.1 g, yield exceeded the amount) as a yellowish solid. LC-MS [M + H] 617.5 (C30H44N6O6S + H, calc: 617.8). Compound H was used directly in the next reaction without purification as a DMF solution. Preparation of Compound I
[0204] A solution of Compound H (21.1 g, ~ 30.4 mmol), mono-tert-butyl malonate (5.9 mL, 36.7 mmol), BOP (16.2 g, 36.7 mmol) and DIEA (14.9 ml, 83.5 mmols) in DMF (100 ml) was kept at room temperature for 1 h. The reaction mixture was diluted with EtOAc (1 L) and extracted with water (500 ml), 5% aq. NaHCO3 (500 ml), water (3 x 500 ml) and sodium chloride saline solution (500 ml). The organic layer was dried over Mg-SO4, filtered, and then evaporated to provide Compound I (24.5 g, 97%) as a yellowish amorphous solid. LC-MS [M + H] 759.6 (C37H54N6O9S + H, calc: 759.9). Compound I was used without further purification. Preparation of Compound J
[0205] Compound I (12.3 g, 16.7 mmols) was dissolved in methanol (100 ml) followed by the addition of a suspension in water (2 ml) of Pd / C (5% by weight, 2.0 g). The reaction mixture was subjected to hydrogenation (Parr apparatus, 482.63 kPa (70 psi H2)) at room temperature for 1 h. The catalyst was then filtered and washed with methanol. The filtrate was evaporated in vacuo to provide Compound J (10.0 g, 99%) as a colorless amorphous solid. LC-MS [M + H] 625.5 (C29H48N6O7S + H, calc: 625.8). Compound J was used without further purification. Preparation of free base oxycodone
[0206] Oxycodone hydrochloride (10.0 g, 28.5 mmol) was dissolved in chloroform (150 mL) and washed with 5% aq. NaHCO3 (50 ml). The organic layer was dried over MgSO4 and evaporated. The residue was dried in vacuo overnight to provide oxycodone free base (8.3 g, 93%) as a white solid. Preparation of Compound K
[0207] A solution of oxycodone free base (6.6 g, 21.0 mmols) in THF (400 mL) was cooled to -20 ° C, followed by the addition of a 0.5 M solution of KHMDS in toluene (46.3 mL, 23.1 mmols). The obtained solution was then added to a solution of 4-nitro-phenyl chloroformate (4.3 g, 21.0 mmols) in THF (100 ml) dropwise over the period of 20 min at -20 ° C. The reaction was maintained at -20 ° C for an additional 1 h, followed by the addition of a solution of Compound J (10.0 g, 16.1 mmols) in THF (200 ml) at -20 ° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvents were evaporated in vacuo. The resulting residue was dissolved in EtOAc (20 ml) and precipitated with ether (1 L). The precipitate formed was filtered, washed with ether and dried in vacuo to provide Compound K (13.6 g, 87%) as an off-white solid. LC-MS [M + H] 966.9 (C48H67N7O12S + H, calc: 966.2). Synthesis of N-1- [2- (oxycodone-6-enol-carbonyl-methyl-amino) -ethylamine]-malonic acid (Compound KC-3)
[0208] Compound K (13.6 g, 14.1 mmol) was dissolved in a 5% m-cresol / TFA (100 mL) mixture. The reaction mixture was kept at room temperature for 1 hour, followed by dilution with ethyl ether (1 L). The formed precipitate was filtered, washed with ether and hexane, and dried in vacuo to provide a TFA salt of Compound KC-3 (11.4 g, 81%) as an off-white solid. LC-MS [M + H] 658.6 (C31H43N7O9 + H, calc: 658.7).
[0209] The crude TFA salt of Compound KC-3 (11.4 g, 11.4 mmol) was dissolved in water (50 mL). The obtained solution was subjected to purification by H-PLC. [Nanosyn-Pack YMC-GEL-ODS A (100-10) C-18 (75 x 500 mm) column; flow rate: 250 mL / minute; injection volume 50 mL; mobile phase A: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA; isocratic elution at 0% B in 4 minutes, gradient elution from 0% to 10% B in 20 minutes, isocratic elution at 10% B in 30 minutes, gradient elution from 10% B to 30% of B in 41 minutes; detection at 254 nm]. Portions containing Compound KC-3 were combined and concentrated in vacuo. The latter's TFA counterion was replaced by a HCI counteron via lyophilization using 0.1N HCI to provide a HCI salt of Compound KC-3 (4.2 g, 41% yield) as a white solid. LC-MS [M + H] 658.6 (C31H43N7O9 + H, calc: 658.7).
[0210] Example 3: Synthesis of N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] (Compound KC-22) and N-1- [3- ( oxycodon-na-6-enol-carbonyl-methyl (amino) -2,2-dimethyl-propylamine] -arginine-glycine malonic (Compound KC-8)
[0211] A solution of 2,2-dimethyl-1,3-diamino propane (Compound L) (48.0 g, 470.6 mmol) in THF (1.0 L) was cooled in an ice bath. Ethyl trifluoroacetate (56 mL, 471 mmol) was added over 30 min via syringe. The mixture was allowed to warm to room temperature, and stirring was continued for 14 h. The mixture was then concentrated in vacuo to half its original volume to give crude Compound M as a THF solution, which was used without further purification in the next reaction. LC-MS [M + H] 199.6 (C7H13F3N2O + H, calc: 199.1). Preparation of Compound N
[0212] The crude solution of Compound M (from the first step) in THF (500 ml) and cooled in an ice bath was added (Boc) 2O in small portions over 15 min. The mixture was stirred at room temperature for 15 h. The reaction was then concentrated in vacuo to give Compound N intermediate in 84% yield (over two steps) (120.0 g, 402.4 mmols) as a viscous oil. LC-MS [M + H] 299.2 (C12H21F3N2O3 + H, calc: 299.2). Compound N was used directly in the next reaction without further purification. Preparation of Compound O
[0213] Compound N (120 g, 403 mmols) was dissolved in CH 3 OH (500 ml) and stirred at room temperature. NaOH (100 mL, 10 N aq.) Was added dropwise. The mixture was then stirred in an oil bath preheated to 50 ° C for 3 h. The mixture being cooled to room temperature and diluted with water (500 ml). The solvents were then removed in vacuo. The residue was extracted with CHCl3 (3 x 100 ml). The combined CHCl3 solution was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude Compound O in 95% yield (77.0 g, 381 mmols). LC-MS [M + H] 203.8 (C10H22N2O2 + H, calc: 203.2). Compound O was used directly in the next reaction without further purification. Preparation of Compound P
[0214] Compound O (97.0 g, 480 mmol) was dissolved in CH2 Cl2 (750 ml). To this was added K2CO3 (75.0 g, 542.6 mmols) in one portion, followed by the careful addition of the 2-nosyl chloride portion (108.0 g, 487.3 mmols). The reaction mixture was stirred at room temperature for 15 h. Then water (200 ml) was added, and the layers were separated. The aqueous layers were extracted again with CH2 Cl2. The combined CH2 Cl2 solution was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using Hexanes / EtOAc 3/1 to give Compound P intermediate in 83% yield (155.0 g, 400.5 mmols) as a white solid. LC-MS [M + H] 388.8 (C16H25N3O6S + H, calc: 388.1). Preparation of Compound R
[0215] Compound P (155.0 g, 400.5 mmols) was dissolved in DMF (500 ml) at room temperature. K2CO3 (83.0 g, 600 mmols) was added in one portion. The mixture was then cooled in an ice water bath. Honey (37.0 mL, 593 mmols) was added in small portions via syringe over 10 min. The mixture was then warmed to room temperature, and stirring was continued at that temperature for another 2 h. The mixture was concentrated in vacuo until ~ 50 ml remained. The remaining mixture containing the intermediate Compound Q was cooled in an ice-water bath. During stirring, thiophenol (100 mL, 978 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 6 h. Water (500 ml) was added. The mixture was extracted with EtOAc (100 ml, then 2 x 500 ml). The combined EtOAc extracts were extracted with 2N HCI (400 ml, then 2 x 200 ml). The HCI extracts were pooled and washed with DCM (500 mL). The acidic solution was then cooled in an ice water bath and basified by adding 10 N NaOH to pH ~ 13. CHCl3 (400 ml, then 2 x 200 ml) were then used to extract the aqueous solution. The combined CHCl3 solution was dried over Na2SO4 and filtered. Evaporation of the solvents in vacuo gave Compound R in 67% yield (58.0 g, 268.5 mmols) as a slightly yellow oil. LC-MS [M + H] 217.6 (C11H24N2O2 + H, calc: 217.2).
[0216] The free base oxycodone (10.0 g, 31.75 mmols) was dissolved in dry THF (150 ml) and the mixture was cooled to -70 ° C using a dry ice / acetone bath. KHMDS (64.0 ml, 128.0 mmols, 0.5 M in to-luene) was added via syringe over 15 min. The mixture was stirred under N2 for an additional 30 min (bath temperature -70 ° C). In a separate flask, 4-nitrophenyl chloroformate (6.4 g, 31.75 mmol) and THF (10 mL) were added. This mixture was also cooled to -70 ° C using a dry ice / acetone bath. The mixture in the first bottle (containing de-protonized oxycodone) was then transferred with a cannula to the second bottle (containing 4-nitrophenyl chloroformate). The transfer took place over ~ 30 min, with the temperature of the two vials being maintained at -70 ° C during the course of the transfer. The resulting reaction mixture was further stirred at -70 ° C for 30 min. A solution of Compound R (6.9 g, 31.94 mmols) in THF (15 ml) was then added with a syringe. The mixture was allowed to stir at -70 ° C for 30 min, and then concentrated in vacuo to obtain a gel as a residue (~ 90% solvent removal). The residue was left to stand at room temperature for 15 h. It was then taken up in EtOAc (200 ml) and washed with aq. sat. NaHCO3 (5 x 50 ml), water (3 x 40 ml) and sodium chloride saline solution (50 ml). The residue from the concentrated EtOAc layer was then purified by chromatography on silica gel, using 10/1 CH3Cl / MeOH to give Compound S in 62% yield (11.0 g, 19.7 mmols). LC-MS [M + H] 559.1 (C30H43N3O7 + H, calc: 558.3). Preparation of N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamineH Compound KC-22)
[0217] A solution of Compound S (11.0 g, 19.7 mmols) was treated with the mixture of TFA and DCM (30 ml / 30 ml) for 2 h at room temperature. The solvents were then removed in vacuo until a volume of ~ 5 ml remained. Et2O (250 ml) was added to precipitate the product. The resulting precipitate was filtered, washed with Et2O (50 ml) and dried to produce Crude KC-22 Compound in 97% yield (11.0 g, 19.2 mmols, 90% purity) as a white solid. LC-MS [M + H] 458.9 (C25H35N3O5 + H, calc: 458.3). Compound KC-22 was used directly in the next reaction without further purification. Preparation of Compound U
[0218] The Boc-Arg (Pbf) -OH solution (9.4 g, 17.8 mmol), Compound KC-22 (11.0 g, 19.7 mmol, 90% pure) and NEt3 (10.0 mL , 71.7 mmols) in DMF (80 ml) was cooled in an ice bath, followed by the addition of HATU (6.8 g, 17.9 mmol) in portions over 10 min. The ice bath was then removed, and the reaction mixture was stirred at room temperature for an additional 1 h. The mixture was diluted with EtOAc (150 ml) and extracted with water (3 x 50 ml) and sodium chloride saline (50 ml). The organic layer was dried over Na2SO4 and filtered; removal of solvents in vacuo provided crude Compound U. Compound U was purified by flash chromatography using CH2 Cl2 and MeOH to give Compound U in 79% yield (13.7 g, 14.2 mmol) as a foamy solid. LC-MS [M + H] 967.5 (C49H71N7O11S + H, calc: 966.5). Preparation of Compound V
[0219] A solution of Compound U (13.7 g, 14.2 mmols) was treated with HCI (4.0 M solution in 1,4-dioxane, 40 ml) at room temperature for 90 min. The solvents were removed in vacuo, and the residue was treated with Et2O (100 ml). The resulting precipitate was removed by filtration, washed with Et2O (2 x 25 ml), and dried to produce crude Compound V in 91% yield (12.1 g, 12.9 mmol) as a white solid. LC-MS [M + H] 867.8 (C44H53N7O9S + H, calc: 866.4). Compound V was used directly in the next reaction without further purification. Preparation of Compound X
[0220] To a solution of Compound V (73.3 g, 78.14 mmol, as HCI salt), N-carboxymethyl malonic acid tert-butyl ester (Compound W) (17.0 g, 78.34 mmol), and NEt3 (33.0 mL, 236.7 mmol ) in DMF (500 mL) at 0 ° C HATU (30.6 g, 80.47 mmol) was added in portions over 10 min. The reaction mixture was stirred at room temperature for 1 h. Water (500 ml) was added and the mixture was extracted with EtOAc (750 ml). The EtOAc extracts were washed with water (2 x 250 ml), NaHCO3 (2 x 200 ml) and sodium chloride saline (250 ml). The organic layer was dried over Na2SO4 and filtered. The solution was concentrated, and the residue was purified through a silica gel column, using a gradient of 1-10% MeOH in CH2 Cl2, to provide Compound X in 43% yield (36.0 g, 33, 8 mmols) as a white solid. LC-MS [M + H] 1067.2 (C53H76N8O13S + H, calc: 1065.5). Preparation of N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamineJ-arpinino-glycolic malonic acid (Compound KC-8)
[0221] Compound X (36.0 g, 33.8 mmol) was treated with a mixture of TFA (60 ml) and m-cresol (2.0 ml) at room temperature. The progress of the reaction was monitored by LC / MS. After 4 h, the mixture was concentrated in vacuo to remove most of the volatiles (~ 90% of the solvent removed). The residue was treated with ethyl ether (1L), and a white precipitate formed. The clear supernatant was removed and the precipitate was washed with ethyl ether (1L). The solid was then concentrated and subjected to HPLC purification. [Nanosyn-Pack Microsorb column (100-10) C-18 (50 x 300 mm); flow rate: 100 mL / minute; injection volume 15 mL; mobile phase A: 100% water, 0.1% TFA; mobile phase B: 100% ACN, 0.1% TFA; elution gradient from 0% to 20% B in 30 min, isocratic elution at 20% B in 30 min, elution gradient from 20% B to 45% B in 35 min; detection at 254 nm]. Portions containing the desired compound were combined and concentrated in vacuo. The residue was dissolved in ACN (60 ml) and 0.1 N HCI (200 ml), and lyophilized to provide Compound KC-8 in 69.6% yield (19.5 g, 23.5 mmols, 99, 4% purity) as a white foam. LC-MS [M + H] 758.5 (C36H52N8O10 + H, calc: 757.4). Biological Data
[0222] Example 4: Pharmacokinetics of Compound KC-8 following the administration of PO to rats This Example demonstrates the release of oxycodone into the plasma when Compound KC-8 is administered orally (PO) to rats.
[0223] Saline solutions of Compound KC-8 (which can be prepared as described in the examples in this document) were dosed as indicated in Table 1 via oral gavage of male Sprague Da-wley rats cannulated in the jugular vein (4 per group) fasted for 16-18 h before oral dosing. At specified time points, blood samples were taken, collected for plasma via 5,400 rpm centrifugation at 4 ° C for 5 min, and 100 microliters (μL) plasma transferred from each sample in a fresh tube containing 2 μL of 50% acid formic. The tubes were vortexed for 5-10 seconds, immediately placed on dry ice, and then stored in a -80 ° C freezer until analysis by HPLC / MS.
[0224] Table 1 and Figure 4 provide the results of exposure to oxycodone from rats administered with different doses of Compound KC-8. The results in Table 1 refer, for each group of rats, as (a) maximum plasma concentration (Cmax) of oxycodone (OC) (mean ± standard deviation), (b) time after administration of Compound KC-8 for reach the maximum oxycodone concentration (Tmax) (mean ± standard deviation) and (c) area under the curve (AUC) from 0 to 24 h (mean ± standard deviation). Tahala 1. Oxycodone Cmax, Tmax and AUC values in rat plasma
[0225] Figure 4 compares the average plasma concentrations over the time of oxycodone release following PO administration to increased dose mice of Compound KC-8.
[0226] The results in Table 1 and Figure 4 indicate that plasma oxycodone concentrations increase proportionally with the dose of Compound KC-8 in rats.
[0227] Example 5: Pharmacokinetics of Compound KC-8 following PO administration to dogs This example demonstrates the release of oxycodone into the plasma when Compound KC-8 was administered orally (PO) to dogs. This Example also compares the release with that of Compound KC-3, an oxycodone prodrug that, unlike Compound KC-8, does not contain twin dimethyl groups in its cyclizable spacer leaving group and lacks glycine in its cleavable portion. trypsin. Plasma oxycodone levels are also compared in dogs administered oxycodone or OxyContin® tablets. Study A.
[0228] Purebred adult / young adult male Beagles fasted overnight. Increasing doses of Compound KC-8 (as shown in Table 2A), 4.15 mg / kg (5.7 µmol / kg) of Compound KC-3 (each of which can be prepared as described in the examples in this document), or 2 mg / kg (5.7 µmols / kg) HCI oxycodone (Johnson Matthey Pharmaceutical Materials, West Deptford, NJ, USA) was administered in water by oral gavage (Table 2A indicates the number of dogs per group). In addition, a group of 4 dogs was administered a 20-mg Tablet of OxyContin® (controlled release of HCI oxycodone) C-ll per dog (NDC 59011-420-10, Purdue Pharma, Stamford, CT, USA). The dose of tablets was followed by approximately 5 ml of water to facilitate swallowing. Doses of oxycodone and OxyContin® tablets were selected to provide approximately equimolar amounts. Blood was collected from each animal through the jugular vein at various times over a 24-h period, centrifuged, and 0.8 mL of plasma transferred to a fresh tube containing 8 µL of formic acid; the samples were vortexed, then immediately placed on dry ice, and stored in a -80 ° C freezer until analysis by HPLC / MS.
[0229] Table 2A and Figure 5 provide results of oxycodone exposure for dogs administered the indicated compounds. The results in Table 2A report, for each group of dogs, as (a) maximum plasma concentration (Cmax) of oxycodone (OC) (mean ± standard deviation), (b) time after the administration of the Compound to reach the concentration oxycodone maximum (Tmax) (mean ± standard deviation) and (c) area under the curve (AUC) from 0 to 24 h (mean ± standard deviation). Table 2A. Cmax, Tmax and AUC values of oxycodone in dog plasma
[0230] The lower limit of quantification was 0.0250 ng / mL Figure 5 compares plasma concentrations over time of oxycodone following PO administration of Compound KC-8, Compound KC-3, OxyContin® or oxycodone HCI tablets to dogs.
[0231] The results in Table 2A and Figure 5 indicate that oral administration of Compound KC-8 to dogs leads to suppression of oxycodone Cmax, delayed oxycodone Tmax and prolonged oxycodone exposure time (AUC) compared to oxycodone administration. Compound KC-8 also provides significantly improved oxycodone release in dog plasma (higher Cmax and AUC) than Compound KC-3. The plasmatic FC profile of oxycodone release by Compound KC-8 administered orally to dogs that resembles that of OxyContin® tablets more than oxycodone; the duration of exposure to the drug is at least as long for Compound KC-8 as for OxyContin® tablets. Study B
[0232] Compound KC-8 was also dosed to dogs in a separate experiment at the doses shown in Table 2B, and samples were collected at various times over a 48-h period. On the other hand, the procedures were the same as those described for Study A.
[0233] Table 2B provides the results of oxycodone exposure for dogs given increasing doses of Compound KC-8. Results are reported as described in Table 2A, except AUC calculated from 0 to 48 h. Table 2B. Cmax, Tmax and AUC values of oxycodone in dog plasma
[0234] The results in Table 2B show that Compound KC-8 has a certain reproducible oral HR profile in dogs that is dose-proportional.
[0235] Example 6: Trypsin-mediated cleavage of the prodrug in vitro and the rate of cyclization of the spacer leaving group of Compound KC-8 This Example assesses the ability of trypsin to cleave the oxycodone Compound KC-8 prodrug. This Example also assesses the rate of cyclization and the release of oxycodone by Compound KC-22, which is identical to that of Compound KC-8 unless Compound KC-22 lacks the trypsin-cleavable portion.
[0236] Compound KC-8 was incubated with bovine pancreas trypsin (Catalog No. T8003, Tipe I, ∼ 10,000 BAEE units / mg protein, Sigma-Aldrich, St. Louis, MO, USA). Specifically, the reactions included 0.761 mM Compound KC-8 • 2HCI, 22.5 mM calcium chloride, 40 to 172 mM Tris pH 8 and 0.25% DMSO with varying trypsin activities. The reactions were conducted at 37 ° C for 24 h. The samples were collected at specific time points, transferred to 0.5% formic acid in acetonitrile to stop trypsin activity and stored at less than -70 ° C until analysis by LC-MS / MS.
[0237] Cyclization release rates were measured following the disappearance rate of Compound KC-22 (2.18 mM initial concentration) in 50 mM of a pH 7.4 phosphate buffer at 20 ° C.
[0238] Table 3 indicates the results of exposure of Compound KC-8 to trypsin. The results are expressed as prodrug half-life when exposed to trypsin (ie, trypsin half-life) in hours and oxycodone formation rate in µmoles per hour per BAEE trypsin unit (µmol / h / BAEE U). Table 3 also indicates the cyclization rate of the KC-22 Compound Spacer Outlet Group. The results are expressed as the half-life of the disappearance of the compound. Table 3. In vitro trypsin cleavage of Compound KC-8, and rate of cyclization of Compound KC-22
[0239] The results in Table 3 indicate that Compound KC-8 can be cleaved by trypsin, and that the spacer leaving group of Compound KC-8 can cyclize, the latter result being shown directly by the cyclization rate of Compound KC-22.
[0240] Example 7; Oral administration of Compound KC-8 coded with trypsin inhibitor Compound 109 in rats This example demonstrates the ability of a trypsin inhibitor to affect the ability of Compound KC-8 to release oxycodone into plasma when Compound KC-8 is administered orally to rats.
[0241] Saline solutions of the compound Compound KC-8 (which can be prepared as described in the examples in this document) were dosed as shown in Table 4. The rats were coded with increasing concentrations of trypsin inhibitor Compound 109 (Catalog No. 3081 , Tocris Bioscience, Ellisville, MO, USA, or Catalog No. WS38665, Waterstone Technology, Carmel, IN, USA) by oral gavage in the cannulated jugular vein of male Sprague Dawley rats (4 per group) who had fasted for 16-18 h before oral dosing. At specified time points, blood samples were taken, collected for plasma via 5,400 rpm centrifugation at 4 ° C for 5 min, and 100 microliters (μL) plasma transferred from each sample in a fresh tube containing 2 µL of 50% acid formic. The tubes were vortexed for 5-10 seconds, immediately placed on dry ice, and then stored in a -80 ° C freezer until analysis by HPLC / MS. Table 4. Codosing of the prodrug Compound KC-8 and trypsin inhibitor Compound 109
[0242] Figure 6A and Figure 6B provide the results of exposure to oxycodone from rats administered different doses of Compound KC-8 in the presence or absence of Compound 109. Figure 6A compares the mean plasma concentrations over time following the release of oxycodone PO from the administration of 5 mg / kg (6 µmol / kg) of the prodrug Compound KC-8 with increasing amounts of trypsin-inhibiting Compound 109 to rats . Figure 6B compares the mean plasma concentrations over time following the release of oxycodone PO from the administration of 50 mg / kg (60 µmol / kg) of the prodrug Compound KC-8 with increasing amounts of trypsin-inhibiting Compound 109 to rats .
[0243] The results in Figure 6A and Figure 6B indicate the ability of Compound 109 to attenuate the ability of Compound KC-8 to release oxycodone in rats in a dose-dependent manner, as indicated by the delayed Cmax and / or Tmax suppression.
[0244] Example 8: Oral administration of a single dose unit and multiple dose units of a composition comprising the prodrug Compound KC-8 and trypsin inhibitor Compound 109 in rats This example demonstrates the effect of oral administration of single and multiple dose units comprising the prodrug Compound KC-8 and trypsin inhibitor Compound 109 to rats.
[0245] Saline solutions of Compound KC-8 (which can be prepared as described in the examples in this document) were dosed orally to rats (4 rats per group) at increasing concentrations ranging from 5 to 50 mg / kg (from 6 to 60 µmol / kg ), in which a single dose represented 5 mg / kg (6 µmol / kg) of Compound KC-8 in the absence of the trypsin inhibitor.
[0246] A second set of rats (4 rats per group) were orally coded with the prodrug Compound KC-8 and trypsin inhibitor Compound 109 (Catalog No. 3081, Tocris Bioscience, or Catalog No. WS38665, Waterstone Technology) as described below and indicated in Table 5. Specifically, the saline solution of a composition comprising 5 mg / kg (6 µmol / kg) Compound KC-8 and 0.5 mg / kg (1 µmol / kg) Compound 109, representative of a dose single unit, was administered by oral gavage to a group of 4 rats. Note that the mole-to-mole ratio of the trypsin-to-prodrug inhibitor (109-to-KC-8) is 0.17-to-1; as such, this dosage unit is referred to herein as a 109-to-KC-8 (0.17-to-1) dose unit. Saline solutions representative of 2 dose units, 3 dose units, 4 dose units, 6 dose units, 8 dose units, and 10 dose units (ie, as shown in Table 5) of the 109-para unit dose -KC-8 (0.17-to 1) were administered similarly to the additional groups of 4 rats.
[0247] All rats were male Sprague Dawley rats cannulated in the jugular vein that had fasted for 16-18 h before oral dosing. The dosing, sampling and analysis procedures were similar to those described in Example 4.
[0248] Table 5 (upper half) and Figure 7A provide plasma oxycodone exposure results for rats administered with 1, 2, 3, 4, 6, 8 and 10 doses of Compound KC-8 in the absence of trypsin inhibitor. Table 5 (bottom half) and Figure 7B provide plasma oxycodone exposure results in rats administered with 1, 2, 3, 4, 6, 8 and 10 dose units of 109-to-KC-8 (0, 17-to-1) unit dose. The oxycodone values Cmax, Tmax and AUC are reported as described in Example 4.
[0249] Figure 7A compares the mean plasma concentration over time of oxycodone release following PO administration of a single dose of multiple doses of Compound KC-8 dosed in the absence of the trypsin inhibitor. Figure 7B compares the mean plasma concentration over time of oxycodone release following PO administration of a single unit dose and multiple dose units of a composition comprising the prodrug Compound KC-8 and trypsin inhibitor Compound 109.
[0250] The results in Table 5, Figure 7A and Figure 7B indicate that the administration of multiple dose units (as exemplified for 1, 2, 3, 4, 6, 8 and 10 dose units of the 109-to-KC-8 unit dose (0.17-to 1)) results in the plasma oxycodone concentration-time FC profile that is not proportional to the single unit dose plasma oxycodone concentration-time FC profile. In addition, the FC profile of the multiple dose units (for example, Figure 7B) was modified compared to the FC profile of the equivalent dosage of prodrug in the absence of the trypsin inhibitor (for example, Figure 7A).
[0251] Example 9: Oral administration of Compound KC-8 coded with trypsin inhibitor Compound 109 in dogs This example demonstrates the ability of a trypsin inhibitor to affect the ability of Compound KC-8 to release oxycodone into plasma when Compound KC-8 is administered orally (PO) to dogs.
[0252] Purebred adult / young adult male Beagles fasted overnight. Compound KC-8 (which can be prepared as described in the examples in this document) was administered at 18.2 mg / kg (22 μ-mol / kg) with or without the codose of 1.8 mg / kg (3.3 µmol / kg) of Compound 109 (Catalog No. 3081, Tocris Bioscience, or Catalog No. WS38665, Waters-tone Technology) in water by oral gavage as indicated in Table 6. The blood was collected, treated and analyzed as in Example 5.
[0253] Table 6 and Figure 8 provide the results of exposure to oxycodone for dogs administered with Compound KC-8, in the presence or absence of Compound 109. The results in Table 6 refer to each group of four dogs, as described in Example 5. Table 6. PO determination of the dog with Compound KC-8 in the absence or presence of Compound 109
[0254] Figure 8 compares the mean plasma concentration over time of oxycodone release following PO administration to dogs of Compound KC-8 with or without a codose of Compound 109 trypsin inhibitor.
[0255] The results in Table 6 and Figure 8 indicate the ability of Compound 109 to attenuate the ability of Compound KC-8 to release oxycodone, both by suppressing Cmax and AUC and delaying Tmax.
[0256] While the present invention has been described with reference to the specific modalities thereof, it should be understood by those skilled in the art that various changes can be made and equivalents can be substituted without changing the true spirit of the scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of material, process, step or process steps to the objective, spirit and scope of the present invention. All such modifications are intended to fall within the scope of the attached claims.

权利要求:
Claims (18)
[0001]
Compound, characterized by the fact that it is N-1- [3- (oxycodone-6-enol-carbonyl-methyl-amino) -2,2-dimethyl-propylamine] -arginine-glycine malonic acid, the compound KC-8 , shown below:
[0002]
Compound according to claim 1, characterized in that it is the compound KC-8, or a pharmaceutically acceptable salt thereof.
[0003]
Compound according to claim 1, characterized by the fact that it is the compound KC-8.
[0004]
Composition, characterized by the fact that it comprises the compound as defined in any one of claims 1 to 3.
[0005]
Composition according to claim 4, characterized in that it comprises the compound KC-8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[0006]
Composition according to claim 4 or 5, characterized in that it still comprises a trypsin inhibitor.
[0007]
Composition according to claim 6, characterized by the fact that the trypsin inhibitor is: (a) a compound of the formula:
[0008]
Composition according to claim 6, characterized in that the trypsin inhibitor is 4- (diaminomethyleneamino) 6-carbamimidoyl-naphthalen-2-yl benzoate (Compound 109).
[0009]
Compound according to any one of claims 1 to 3, or a composition according to any one of claims 4 to 8, characterized in that it is for use in medical therapy.
[0010]
A compound according to any one of claims 1 to 3, or a composition according to any one of claims 4 to 8, characterized in that it is for use in a method of treating or preventing pain.
[0011]
Compound according to any one of claims 1 to 3, or a composition according to any one of claims 4 to 8, characterized in that it is in the preparation of a medicament for the treatment or prevention of pain.
[0012]
A compound according to any one of claims 1 to 3, or its composition, characterized by the fact that it is for use in a method to reduce potential abuse, said method comprising: combining said compound with a trypsin inhibitor, wherein said trypsin inhibitor reduces a user's ability to release oxycodone from said compound by the addition of trypsin.
[0013]
Dose unit comprising a composition as defined in any one of claims 6 to 8, characterized in that the compound and trypsin inhibitor are present in the unit dose in an amount efficient to provide the pre-selected pharmacokinetic (FC) profile at following ingestion.
[0014]
Dose unit according to claim 13, characterized in that the dose unit provides a pre-selected FC profile after ingesting at least two dose units.
[0015]
Method of preparing a unit dose, the method characterized by the fact that it comprises: combine in one dose unit: a compound as defined in any one of claims 1 to 3; a trypsin inhibitor that interacts with trypsin that mediates the enzymatically controlled release of oxycodone from the compound; wherein the compound and the trypsin inhibitor are present in the dose unit in an amount efficient to attenuate the release of oxycodone from the compound in such a way that the intake of multiple dose units by a patient does not provide a proportional release of oxycodone .
[0016]
Method for identifying a compound and an inhibitor of trypsin suitable for formulation in a unit dose, the method characterized by the fact that it comprises: combining a compound as defined in any one of claims 1 to 3, a trypsin inhibitor, and trypsin in a reaction mixture, and detect the conversion of the compound to oxycodone, wherein a decrease in the conversion of the compound in the presence of the trypsin inhibitor compared to the conversion of the compound in the absence of the trypsin inhibitor indicates that the compound and the trypsin inhibitor are suitable for formulation in a unit dose.
[0017]
Method for identifying a compound and a trypsin inhibitor suitable for the formulation of a unit dose, characterized by the fact that it comprises: Administer an animal tissue that has been removed from the animal with a compound as defined in any one of claims 1 to 3 and a trypsin inhibitor, and Detect the conversion of the compound, in which a decrease in the conversion of the compound in the presence of the trypsin inhibitor when compared to the conversion of the compound in the absence of the trypsin inhibitor indicates that the compound and the trypsin inhibitor are suitable for formulation in a unit of dose.
[0018]
Method for identifying a compound and a trypsin inhibitor suitable for the formulation of a unit dose, characterized by the fact that it comprises: Non-therapeutically administering to a non-human animal a compound as defined in any one of claims 1 to 3 and a trypsin inhibitor, and Detect the conversion of the compound to oxycodone, where a decrease in the conversion of the compound in the presence of the trypsin inhibitor when compared to the conversion of the compound in the absence of the trypsin inhibitor indicates that the compound and the trypsin inhibitor are suitable for formulation in a dose unit.

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AU2012205733A1|2013-05-09|

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法律状态:
2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-10-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2019-11-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-02-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-09-01| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-12-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/01/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161431781P| true| 2011-01-11|2011-01-11|

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US61/431,781|2011-01-11|

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