US 20110077222A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0077222 A1 Schaefer et al. (43) Pub. Date: Mar. 31, 2011

(54) SUSTAINED-RELEASE OPIATE AND OPIATE Publication Classification DERVATIVE COMPOSITIONS (51) Int. Cl. (75) Inventors: Carl J. Schaefer, Crestwood, MO A63L/485 (2006.01) (US); Gary L. Cantrell, Troy, IL C07F 9/09 (2006.01) (US) A6IP 25/04 (2006.01) (73) Assignee: Mallinckrodt Inc., Hazelwood, (52) U.S. Cl...... 514/81: 546/23 MO (US) (21) Appl. No.: 12/894,203 (57) ABSTRACT The present invention provides Sustained-release opiate com (22) Filed: Sep. 30, 2010 positions. In particular, the present invention provides Sus tained-release opiate compositions that include an opiate Related U.S. Application Data attached to a blood albuminbinder. The present invention also (60) Provisional application No. 61/247,076, filed on Sep. relates to methods of administering an opiate with a Sustained 30, 2009. release pharmacokinetic profile. US 2011/0077222 A1 Mar. 31, 2011

SUSTAINED-RELEASE OPIATE AND OPIATE SUMMARY OF THE INVENTION DERVATIVE COMPOSITIONS 0008. One aspect of the present invention encompasses a Sustained-release opiate composition that includes an opiate, CROSS REFERENCE TO RELATED a non-peptide blood albumin binder, and a connecting bridge APPLICATIONS attached to the opiate and to the non-peptide blood albumin 0001. This application claims the benefit of U.S. Provi binder. Without being bound to any particular theory, after sional Application No. 61/247,076 filed Sep. 30, 2009, which administering the composition to a patient, the non-peptide is incorporated herein in its entirety. blood albumin binder non-covalently binds to circulating albumin protein in the bloodstream of the patient. The opiate FIELD OF THE INVENTION and binding bridge, which are attached to the non-peptide 0002 The present invention generally relates to sustained blood albumin binder, are similarly bound to the circulating release opiate compositions. In particular, the present inven albumin protein. In this bound state, the opiate is rendered tion relates to Sustained-release opiate compositions that inactive until released into the bloodstream. The bonds that include an opiate attached to a blood albumin binder. attach the opiate to the binding bridge are cleaved as a func tion of time, and the opiate is released into the bloodstream to BACKGROUND OF THE INVENTION exert its therapeutic effect. It has been discovered surprisingly that an opiate released in this manner exhibits essentially the 0003) Opiates are highly effective and widely used nar same efficacy as the same opiate administered in isolation. cotic compounds. Although these compounds have a power 0009. Without being bound to any particular theory, the ful and essentially immediate effect, the benefits of opiate elapsed time at which the opiate is released is influenced by a administration are somewhat limited by relatively short half number of factors including the chemical properties of the life of opiates due to rapid clearance by the hepatic and binding bridge and the opiate, as well as the chemical prop urinary systems. erties of the patient's bloodstream, such as pH. Because blood 0004 Existing sustained-release opiate formulations pH is actively maintained at a constant value, the pharmaco entail administering the opiate active compound as an oral kinetic release profile is highly reliable. In another aspect, the composition that includes the opiate active compounds Sustained-release opiate composition includes an opiate, a coated with a degradable coating that releases the opiate non-peptide blood albumin binder such as diphenylcyclohex active compound with a specified release profile. However, anol, and a connecting bridge Such as phosphate diester. Yet these formulations are relatively expensive to produce and are another aspect provides a sustained-release opiate composi particularly Vulnerable to tampering, posing the danger of tion that includes an opiate chosen from Oxycodone, oxymor overdose. Further, the release profile of oral sustained release phone, hydrocodone, hydromorphone, naloxone, nalbuphine, compounds are relatively unpredictable due to wide variation nalmefene, buprenorphine, and naltrexone, a non-peptide in the chemical conditions in the stomach due to the ingestion blood albumin binder Such as diphenylcyclohexanol, and a of food, alcohol, or other pharmaceutically active com connecting bridge Such as phosphate diester. pounds. 0010. An additional aspect provides a sustained-release 0005. Although the opiate may be released in a sustained opiate composition that includes a first compound and a sec release profile using an orally administered composition, the ond compound. The first compound includes a first opiate, a opiate is still rapidly cleared from circulation upon release. first non-peptide blood albumin binder, and a first connecting Thus the sustained-release period is limited to the amount of bridge attached to the first opiate and to the first non-peptide time that the oral composition is resident in a region of the blood albumin binder. The second compound includes a sec digestive tract possessing Suitable conditions for the release ond opiate, a second non-peptide blood albuminbinder, and a and absorption of the opiate active compounds. second connecting bridge attached to the second opiate and to 0006. The half-life of any active compound in circulation the second non-peptide blood albumin binder. is affected by the affinity of the compound for long-lived 0011. Another additional aspect provides a sustained-re circulating proteins such as blood albumin or blood cell Sur lease opiate composition that includes a first opiate, a second face proteins. Recent Sustained-release formulations have attempted to exploit this phenomenon by coupling active opiate, a non-peptide blood albumin binder, and a connecting compounds with antibodies, antibody fragments, and other bridge attached to the first opiate, to the second opiate, and to peptides that have a binding affinity for blood albumin or the non-peptide blood albumin binder. other circulating proteins. In addition to extending the half 0012 Still another aspect provides a method of adminis life of active compounds, the chemical properties of the tering an opiate to a human Subject with a Sustained release bloodstream such as pH are actively maintained at constant pharmacokinetic profile relative to a pharmacokinetic profile levels, resulting in a more reliable release profile than oral of the opiate administered in isolation. In this aspect, the Sustained release compositions. To date, this approach has method includes providing a Sustained-release opiate compo been limited to active compounds that are Small peptides. sition that includes an opiate, a non-peptide blood albumin 0007. A need exists in the art for a sustained-release opiate binder, and a connecting bridge attached to the opiate and to composition that incorporates a circulating protein binding the non-peptide blood albumin binder. The method further compound to extend the halt-life of the opiate in circulation includes administering the Sustained-release opiate composi and to provide a reliable pharmacokinetic release profile. tion to the human Subject. However, the efficacy of opiates and opiate derivatives are 0013. Other features and iterations of the invention are notoriously sensitive to Small changes to their chemical struc described in more detail below. tures. A need exists in the art for a Sustained-release formu lation that incorporates a circulating protein binding com DETAILED DESCRIPTION pound without compromising the efficacy of the opiate active 0014. The present invention provides sustained-release compound. opiate compositions and methods of administering the com US 2011/0077222 A1 Mar. 31, 2011 positions to a human patient. In particular, the present inven opiate compositions may include adulmine, , tion provides Sustained-release opiate compositions that , benzylmorphine, , bicuculine, bicucine, include an opiate attached to a blood albumin binder using a , buprenorphine, butorphanol, , capau connecting bridge. Upon administration, the blood albumin rine, , , codamine, , cop binder component of the composition non-covalently binds to tisine, coreximine, corlumine, corybulbine, cory cavamine, circulating blood albumin. The connecting bridge is cleaved corycavine, , corydine, corytuberine, cularine, as a function of time, thereby releasing the opiate into circu cotamine, , , cycloartenone, lation, where it exerts its therapeutic effect. It has been dis cyclolaudenol, dehydroreticuline, desomorphine, dextropro covered that administering the opiate attached to a blood poxyphene, dextrorphanol, diacetylmorphine, , albuminbinder significantly extends the half-life of the opiate , dipropanoylmorphine, epiporphyroX in the blood without significantly degrading the therapeutic ine, ethylmorphine, eupaverine, fagarine, fentanyl, , homochelidonoine, hydrocodone, hydrocotamine, hydro efficacy of the opiate. morphone, hydroxythebaine, isoboldine, isocorybulbine, iso 0015 Without being bound to any particular theory, when corydine, isocorypalmine, , laudanidine, lauda bound to blood albumin, the Sustained-release opiate compo nine, , levorphanol, , , sition is protected from processes of hepatic and nephritic methadone, , nalbuphine, nalmefene, naloxone, elimination that rapidly remove unprotected opiates from the maltrexamine, C.-naltrexol, B-maltrexol, naltrexone, naph bloodstream. In addition, when the Sustained-release opiate thaphenanthridine, narceline, narceinone, narcotoline, narco composition is bound to blood albumin, the opiate component tine, neopine, nicomorphine, norlaudanosoline, norsangui is rendered inactive until the connecting bridge is hydrolyzed, narine, , , , oxycodone, thereby releasing the opiate in its active form into the blood oxymorphone, oxysanguinarine, palaudine, , stream. Thus, the blood albumin functions as a pool of unre leased opiate that circulates in relatively close proximity to papaveraldine, papaverrubine, perparin, pethidine, phenan target receptors. Unlike previous Sustained-release threne, phtalide-isoquinoline, porphyroXine, , formulations that rely on the degradation of a coating layer in pseudocodeine, , , , the digestive system to extend the release of active com sinoacutine, , , somniferine, Stepholi pounds into the circulatory system, embodiments of the Sus dine, tapentadol, tetrahydroprotoberberine, , trama tained-release opiate composition release opiate directly into dol, and Xanthaline. In exemplary embodiments, the opiate circulation. included in an embodiment of the Sustained-release opiate 0016. The sustained release profile of the opiate composi compositions may be selected from oxycodone, oxymor tion may be specified by administering a composition that phone, hydrocodone, hydromorphone, nalbuphine, naloxone, includes a mixture of compounds in which each compound buprenorphine, and naltrexone. includes the opiate attached to the blood albumin binders 0020. Any of the opiates included in the embodiments of using one of at least two different connecting bridges. the Sustained-release opiate compositions may have a (-) or Because each of the different connecting bridges may be (+) orientation with respect to the rotation of polarized light, cleaved in the bloodstream at different times, the release depending upon whether the starting Substrate has (-) or (+) profile of the combined compounds is different from the optical activity. More specifically, each chiral center may release profile of any of the single compounds administered in independently have an R or an S configuration. isolation. Alternatively, the Sustained release pharmacoki 0021. As an illustrative example, an embodiment of the netic profile of the opiate composition may be specified by Sustained release opiate composition may include a morphi administering a composition in which two or more opiates are nan compound. For the purposes of discussion, the ring atoms attached to each blood albumin binder using a connecting of a morphinan compound may be numbered as diagramed in bridge. In other embodiments, a Sustained release composi Formula (I) below. Morphinan compounds have asymmetric tion may include two or more different opiate compounds that centers and the core morphinan compound may have at least are attached to the same albumin binding bridge. four chiral carbons: C-5, C-13, C-14, and C-9. In various 0017. The present invention further provides a method of embodiments, the configuration of the chiral carbons C-5, administering an opiate in a Sustained-release pharmacoki C-13, C-14, and C-9 may be RRRR, RRSR, RRRS, RRSS, netic profile that includes administering a Sustained-release RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, composition that includes an opiate attached to a blood albu SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the minbinder using a connecting bridge. Because the Sustained C-16 carbons are both either on the alpha face or the beta face release opiate composition is inactive when bound to blood of the molecule. albumin, a higher dosage may be administered relative to the (I) dosage recommended for the opiate administered in isolation. Thus, the Sustained-release opiate composition releases an effective amount of opiate into the bloodstream with a more uniform concentration over time and for a more Sustained period of time than the opiate administered in isolation. 0018. The sustained-release opiate compositions, as well as the opiates, blood albumin binders, and connecting bridges, are described in detail below. (I) Opiates 0019. The opiate included in the embodiments of the sus tained-release opiate compositions may be selected from 0022. In various embodiments of the sustained-release opium, natural opium derivatives, semi-synthetic opium opiate compositions, the opiate is attached to a connecting derivatives, and synthetic opium derivatives. In particular, the bridge that is also attached to a blood albumin binder. In one opiates included in the embodiments of the Sustained-release embodiment, the opiate is covalently bonded to the connect US 2011/0077222 A1 Mar. 31, 2011

ing bridge. The covalent bond used to attach the opiate to the tion of the Sustained-release opiate composition. Interference connecting bridge is selected to allow the bond to be broken with the binding of the blood albuminbinder may be due to at or cleaved after a specified time in the bloodstream, causing least several factors including the direct influence of the con the opiate to be released in an active form into the blood necting bridge on the chemical properties of the blood albu stream. The covalent bond used to attach the opiate to the min binder, affinity of the binding bridge itself for blood connecting bridge is further selected such that the efficacy of albumin, and the interference of the opiate attached to the the opiate in its active form is not significantly degraded due binding bridge with the blood albumin binder. The chemical to chemical reactions such as hydrolysis used to break the properties of the connecting bridge Such as electronegativity covalent bond attaching the opiate to the connecting bridge. and the physical properties of the connecting bridge Such as In an exemplary embodiment, the covalent bond used to molecule length and bond flexibility are selected to minimize attach the opiate to the connecting bridge is an ester bond that interference with the binding of the blood albumin binder to is hydrolyzed to release the opiate into the bloodstream in its the circulating albumin protein. active form. 0030. In addition, the binding bridge is selected on the 0023 The covalent bonds selected to attach the opiate to basis of its ability to degrade within an elapsed time in the the connecting bridge in various embodiments are described bloodstream after administration of the Sustained-release opi in detail in Section III below. ate composition. Because active opiate is released into the bloodstream after the cleaving of the bonds attaching the (II) Blood Albumin Binder opiate to the binding bridge, this elapsed time determines the release profile of the opiate into the bloodstream. This desired 0024. The blood albumin binders used in various embodi elapsed time may range from a relatively short period of about ments of the Sustained-release opiate composition include one hour up to the half-life of blood albumin in the serum of various non-peptide compounds having a strong affinity for a human patient, or about twenty days. In other embodiments, binding to blood albumin. Without being bound to any par the binding bridge may be selected to degrade and release ticular theory, the blood albuminbinder non-covalently binds opiate into the bloodstream within a elapsed time ranging to the blood albumin and effectively binds any other attached between about one hour and about four hours, between about components of the Sustained-release opiate composition to two hours and about six hours, between about four hours and the blood albumin as well, including the opiate and the bind about twelve hours, between about six hours and about eigh ing bridge. teen hours, between about twelve hours and about one day, 0025. In addition, blood albumin binders used in the sus between about eighteen hours and about three days, between tained-release opiate compositions possess a specific affinity about 2 days and about 4 days, between about 3 days and for blood albumin relative to other blood proteins or other about 5 days, between about 4 days and about 8 days, between tissue proteins, so as to avoid the binding of the Sustained about 6 days and about 10 days, between about 8 days and release opiate composition to undesired proteins such as about 12 days, between about 10 days and about 14 days, blood cell receptor proteins, chemokines, antibodies, or other between about 12 days and about 16 days, and between about circulating or non-circulating protein structures. 15 days and about 20 days. 0026 Blood albumin binders suitable for use in the sus 0031. Further, the binding bridge is selected such that the tained-release opiate compositions may include but are not cleaving of the bond attaching the binding bridge to the opiate limited to one or more functional groups. Non-limiting does not degrade the efficacy of the active opiate in the blood examples of suitable functional groups include aliphatic and stream relative to the efficacy of the opiate administered in aryl groups, in which each aliphatic and aryl group includes isolation. between about 1 and about 60 carbons, as well as any one or more Substituents including but not limited to a nitrogen, an 0032 Suitable compounds for use as binding bridges in oxygen, a Sulfur, a halogen, an alkyl group, an amide, an ester, various embodiments include but are not limited to functional and a sulfonamide. In an exemplary embodiment, the blood groups chosen from phosphate monoesters, phosphate albumin binders may include but are not limited to diphenyl diesters, phosphate triesters, carbonates, Sulphonates, boric cyclohexanol, phenylhexanol, biphenylpropanol, and 1,4-tet acid esters, and diesters of dicarboxylic acids such as oxalic, rahydronaphthalene. citric, glutaric, tartaric, malonic, aspartic, glutamic, Suberic, 0027. The blood albumin binders included in the sus fumaric, maleic. Succinic, and adipic acids. In an exemplary tained-release opiate composition are covalently bonded to embodiment, the binding bridge includes phosphate diesters the connecting bridge in a manner that does not interfere with as a functional group. the release of the opiate into the bloodstream upon cleaving 0033. In an embodiment, the binding bridge is attached to the connecting bridge. Covalent bonds suitable for attaching the opiate using an ester bond formed at a hydroxy group the blood albumin binder to the connecting bridge are attached to the opiate. The hydroxy group attached to the described in detail in Section III below. opiate may be a group that naturally occurs on the opiate, or the hydroxy group may be added to the opiate for the purpose (III) Connecting Bridge of attaching the binding bridge. The place of attachment of the binding bridge to the opiate may affect the degradation of the 0028. The connecting bridge is attached to both the opiate bond connecting the binding bridge to the opiate due to the and to the blood albumin binding bridge using covalent chemical interaction of various moieties of the opiate that are chemical bonds. The particular connecting bridges used in in close proximity to the place of attachment. In another various embodiments of the Sustained-release opiate compo embodiment, the place of attachment of the connecting bridge sition are selected based on at least several criteria. to the opiate may be selected in order to achieve a desired 0029. A connecting bridge may be selected so that it does pharmacokinetic profile. not significantly interfere with the binding of the blood albu 0034. As an illustrative example, if the composition min binder with the blood albumin protein after administra includes oxymorphone, shown as Formula (II) below, the US 2011/0077222 A1 Mar. 31, 2011 binding bridge may be attached at the hydroxy group attached necting bridge, the process disclosed by U.S. Pat. No. 6,676, at C-3 or at C-14. In addition, the binding bridge may be 929 follows the general scheme illustrated below for a phos attached at the oxygen attached at C-6. phate diester binding bridge:

(II) NE H3C -S-1a OH CH | -- -e- R -N CH O (III) CH R (IV) N=S-N O /R P-O 0035. In another illustrative example, if the composition includes buprenorphine, shown as Formula (IIA) below, the O binding bridge may be attached at the hydroxy group attached R at C-3 or at C-20. (V)

(ILA)

HQ /R. NH4" O o=1–0 OFP O f h R l, (VII) (VI) 0038 in which: 0.039 R is an opiate, described in Section (I) above, to 0036. In other embodiments, the sustained-release opiate be included in the Sustained-release opiate composition, composition may include compounds made up of more than and one binding bridge functional group in order to specify the 0040 R is a blood albuminbinder, described in Section desired opiate pharmacokinetic release profile. For example, (II) above, to be included in the sustained-release opiate a Sustained-release opiate composition may include a mixture composition. of compounds that include binding bridges that degrade after 0041. In general, the opiate R1 is combined with 2-cyano a relatively short elapsed time as well as compounds that ethyl N,N-diisopropylchlorophosphoramidite, resulting in a include binding bridges that degrade after a relatively longer phosphoramidite intermediate product, shown as Formula elapsed time. Upon administration, the opiates attached to the (IV) above. The amidite moiety is replaced by the blood shorter-lived connecting bridges would be released shortly albumin-binding moiety to yield a phosphate intermediate after administration. As the active opiate is metabolized and product, shown as Formula (V) above, which still includes an otherwise removed from circulation, additional opiate attached cyanoethyl group. The cyanoethyl group is Subse attached to the longer-lived connecting bridges would be quently replaced by an ionically bonded ammonium ion, as released. In this embodiment, a more Sustained and uniform shown in Formula (VI) above. A strong acid is added to opiate pharmacokinetic release profile results from the displace the ammonium ion with a hydrogen anion, resulting replacement of the metabolized opiate with newly released in the Sustained-release opiate composition, shown above in opiate. Formula (VII). 0042. Although the method of making the sustained (IV) Methods of Making Sustained Release Opiate release opiate composition illustrated above included a phos Compositions phate diester as the binding bridge, any one of the binding bridges described in Section (III) above may be used in other 0037. The sustained-release opiate composition may be embodiments of the method with appropriate modifications. made using any techniques known in the art. As an illustrative 0043. For the synthesis of sustained-release opiate com example, the Sustained-release opiate composition may be pounds that include opiates possessing more than one made using techniques disclosed by U.S. Pat. No. 6,676,929, attached hydroxy group, those hydroxy groups for which no which is hereby incorporated by reference herein in its attachment of blood albumin binders is desired may be entirety. Although the specific steps of the synthesis process chemically modified with moieties such as t-butyl groups to may vary depending on at least several factors including the prevent the attachment of blood albumin binders during the specific opiate compound, blood albumin binder, and con synthesis of the Sustained-release opiate compositions. Yet

US 2011/0077222 A1 Mar. 31, 2011

described above. The method further includes administering pregelatinized and modified Starches thereof, Sweeteners, the Sustained-release opiate composition to the human Sub clays, such as bentonite, micro-crystalline cellulose, algi ject. The Sustained-release opiate composition may be admin nates, Sodium starch glycolate, gums such as agar, guar, istered by methods including but not limited to intravenous locust bean, karaya, pecitin, and tragacanth. Suitable effer injection, intramuscular injection, infusion, transdermal Vescent disintegrants include but are not limited to sodium absorption, ingestion, inhalation, vaginal absorption and rec bicarbonate in combination with citric acid, and sodium tal absorption. In an exemplary embodiment, the Sustained bicarbonate in combination with tartaric acid. release opiate composition is administered by intravenous 0055. Non-limiting examples of preservatives include injection. antioxidants, such as a-tocopherol or ascorbate, and antimi 0049. Because the opiate is released with a sustained crobials, such as parabens, chlorobutanol or phenol. release pharmacokinetic profile, the Sustained-release opium 0056. Diluents suitable for use include but are not limited composition may be administered to the human Subject at an to pharmaceutically acceptable Saccharides such as Sucrose, effective dosage that is higher than the recommended dosage dextrose, lactose, microcrystalline cellulose, fructose, Xyli for the corresponding opiate administered in isolation. Upon tol, and Sorbitol; polyhydric alcohols; Starches; pre-manufac administration, at least Some fraction of the opiate included in tured direct compression diluents; and mixtures of any of the the Sustained-release opiate composition is bound to the foregoing. blood albumin of the human subject in an inactive form for 0057 Suitable flavor-modifying agents include but are not later release. Therefore, in order to achieve a therapeutically limited to synthetic flavor oils and flavoring aromatics and/or effective blood concentration of opiate, a higher dosage may natural oils, extracts from plants, leaves, flowers, fruits, and be administered. However, because the opiate is released in combinations thereof. Other non-limiting examples of flavors active form with a Sustained release pharmacokinetic profile, include cinnamon oils, oil of wintergreen, peppermint oils, the Sustained-release opiate composition may be adminis clover oil, hay oil, anise oil, eucalyptus, Vanilla, citrus oils tered less frequently compared to the corresponding opiate Such as lemon oil, orange oil, grape and grapefruit oil, fruit administered in isolation. essences including apple, peach, pear, Strawberry, raspberry, 0050 Formulations of the various embodiments of the cherry, plum, pineapple, and apricot. Sustained-release opiate compositions are dependent on a 0.058 Non-limiting examples of sweeteners include glu number of factors including but not limited to the method of cose (corn syrup), dextrose, invert Sugar, fructose, and mix administration of the composition. As an illustrative example, tures thereof (when not used as a carrier); saccharin and its a formulation of the Sustained-release opiate composition to various salts such as the sodium salt; dipeptide Sweeteners be administered by ingestion may include excipients such as Such as aspartame; dihydrochalcone compounds, glycyr binders and taste masking agents. Formulations of various rhizin; Stevie rebaudiana (Stevioside); chloro derivatives of embodiments of the Sustained-release opiate composition are Sucrose Such as Sucralose; Sugar alcohols such as Sorbitol, described below. mannitol, Sylitol, hydrogenated Starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1,2,3-oxathiazin (V) Formulations 4-one-2,2-dioxide, particularly the potassium salt (ac 0051. Formulations of various embodiments may include esulfame-K), and Sodium and calcium salts thereof. the Sustained-release opiate composition, along with an 0059 Non-limiting examples of lubricants include mag excipient. Non-limiting examples of excipients include bind nesium Stearate, calcium Stearate, Zinc Stearate, hydrogenated ers, fillers, non-effervescent disintegrants, effervescent disin Vegetable oils, Sterotex, polyoxyethylene monostearate, talc, tegration agents, preservatives, diluents, flavor-modifying polyethylene glycol, Sodium benzoate, sodium lauryl Sulfate, agents, Sweeteners, lubricants, dispersants, coloring agents, magnesium lauryl Sulfate, and light mineral oil. taste masking agents, pH modifiers. and combinations of any 0060 Dispersants may include but are not limited to of these agents. starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, 0052. Non-limiting examples of binders suitable for the bentonite, purified wood cellulose, sodium starch glycolate, formulations of various embodiments include starches, isoamorphous silicate, and microcrystalline cellulose as high pregelatinized starches, gelatin, polyvinylpyrrolidone, cellu HLB emulsifier surfactants. lose, methylcellulose, sodium carboxymethylcellulose, eth 0061. Depending upon the embodiment, it may be desir ylcellulose, polyacrylamides, polyvinyloxoazolidone, poly able to include a coloring agent. Suitable color additives vinylalcohols, C12-C18 fatty acid alcohols, polyethylene include but are not limited to food, drug and cosmetic colors glycol, polyols, Saccharides, oligosaccharides, polypeptides, (FD&C), drug and cosmetic colors (D&C), or external drug oligopeptides, and combinations thereof. The polypeptide and cosmetic colors (Ext. D&C). These colors or dyes, along may be any arrangement of amino acids ranging from about with their corresponding lakes, and certain natural and 100 to about 300,000 Daltons. derived colorants may be suitable for use in various embodi 0053 Non-limiting examples of fillers include carbohy mentS. drates, inorganic compounds, and polyvinylpirrolydone. 0062 Taste-masking agents include but are not limited to Other non-limiting examples of fillers include dibasic cal cellulose hydroxypropyl ethers (HPC) such as Klucel(R), Nis cium sulfate, tribasic calcium Sulfate, starch, calcium carbon swo HPC and PrimaFlo HP22; low-substituted hydroxypro ate, magnesium carbonate, microcrystalline cellulose, diba pyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers sic calcium phosphate, tribasic calcium phosphate, (HPMC) such as Seppifilm-LC, Pharmacoat(R), Metolose SR, magnesium carbonate, magnesium oxide, calcium silicate, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and talc, modified Starches, lactose, Sucrose, mannitol, and Sorbi Benecel MP843; methylcellulose polymers such as Metho tol. cel(R) and Metolose(R); Ethylcelluloses (EC) and mixtures 0054 Non-limiting examples of non-effervescent disinte thereof such as E461, Ethocel(R), AqualonR)-EC, Surelease: grants include starches Such as corn starch, potato starch, Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyeth US 2011/0077222 A1 Mar. 31, 2011

ylcelluloses such as Natrosol(R); carboxymethylcelluloses and cream that includes but is not limited to the sustained-release salts of carboxymethylcelluloses (CMC) such as Aualon(R)- opiate composition Suspended or dissolved in one or more CMC; polyvinyl alcohol and polyethylene glycol co-poly carriers. Non-limiting examples of Suitable carriers for trans mers such as Kollicoat IRR); monoglycerides (Myverol), trig dermal embodiments include mineral oil, liquid petrolatum, lycerides (KLX), polyethylene glycols, modified food starch, white petrolatum, propylene glycol, polyoxyethylene, poly acrylic polymers and mixtures of acrylic polymers with cel oxypropylene compound, emulsifying wax, Sorbitan lulose ethers such as EudragitR) EPO, Eudragit(R) RD100, and monostearate, Polysorbate 60, cetyl esters wax, cetearyl alco EudragitR) E 100; cellulose acetate phthalate; sepifilms such hol, 2-octyldodecanol, benzyl alcohol and water. For these as mixtures of HPMC and stearic acid, cyclodextrins, and embodiments, the molecular weight of the composition may mixtures of these materials. In other embodiments, additional range from about 1 to about 50 Daltons. taste-masking agents contemplated are those described in U.S. Pat. Nos. 4,851,226, 5,075,114, and 5,876,759, each of (V) Exemplary Embodiments which is hereby incorporated by reference in its entirety. 0067. The molecules of various embodiments of the sus 0063) Non-limiting examples of pH modifiers include tained-release opiate compositions are described generally by Sodium carbonate and Sodium bicarbonate. Formula (XII) below: 0064. In those embodiments administered orally, the sus tained-release opiate compositions may be administered in A-B-X (XII): any orally acceptable dosage form including, but not limited in which A is a blood albumin binder described in Section II, to, capsules, tablets, aqueous Suspensions, or Solutions. Cap B is a connecting bridge described in Section III, and X is an sule and tablet formulations may include, but are not limited opiate described in Section I. For those opiates having more to binders, lubricants, and diluents. Aqueous suspension for than one hydroxy group, the connecting bridge B may attach mulations may include but are not limited to dispersants, to the opiate X at any one of its hydroxy groups, as described flavor-modifying agents, taste-masking agents, and coloring in Section (III) above. In other embodiments, a hydroxy agents. group may be attached to the opiate X at a specified location 0065 For those embodiments using rectal absorption as a to provide a binding site for the binding bridge B. Because the method of administration, the Sustained-release opiate com moieties in the vicinity of the point of attachment of the position may be administered in the form of rectal Supposi binding bridge B to the opiate X may affect the release prop tories. In these embodiments, the composition may include a erties of the opiate upon administration, a composition in suitable non-irritating excipient that is solid at room tempera which the connecting bridge is connected at one hydroxy ture but liquid at rectal temperature and therefore will melt in group on the opiate is considered a different embodiment the rectum to release the drug. Non-limiting examples of compared to a composition in which the connecting bridge is Suitable excipients for rectal Suppository embodiments connected to a different hydroxy group at a different location include cocoa butter, beeswax, and polyethylene glycols. on the opiate. 0066 For transdermally absorbed embodiments, the com 0068. Non-limiting examples of embodiments of the sus position may be formulated as a suitable ointment, lotion, or tained-release opiate compositions are listed in Table I below:

TABLE I

Exempl Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure diphenylcyclohexanol phosphate oxymorphone diester attachedC-3 at ( ) O o--o NCH HO OH O

O

diphenylcyclohexanol phosphate oxymorphone O diester attached at C-14 ( ) O ( ) | O o--oHO HCN OH US 2011/0077222 A1 Mar. 31, 2011

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol phosphate oxymorphone O diester attached at O- –o NCH C-3 HO OH O

O phenylhexanol phosphate oxymorphone O diester attached at C-14 O O O- – O HO HCN OH biphenylpropanol phosphate oxymorphone diester O attached at C-3 O-P-O NCH 3 HO OH O

O biphenylpropanol phosphate oxymorphone O diester attached at C-14 O O O- -O

HO HCN OH

1,4- phosphate oxymorphone O tetrahydronaphthalene diester attached at O-P-O NCH C-3 HO OH O

O US 2011/0077222 A1 Mar. 31, 2011

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- phosphate oxymorphone O tetrahydronaphthalene diester attached at C-14 O O o--o COr HO HCN OH diphenylcyclohexanol carbonate oxymorphone attached at C-3 o-I-o NCH O OH O

O diphenylcyclohexanol carbonate oxymorphone O attached at C-14 O o--o O

HCN OH

phenylhexanol carbonate oxymorphone O attached at C-3 o-l-o NCH

OH O

O phenylhexanol carbonate oxymorphone O attached at C-14 O O

HCN OH US 2011/0077222 A1 Mar. 31, 2011 10

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure biphenylpropanol carbonate oxymorphone attached at O C-3 O O NCH

OH O

O biphenylpropanol carbonate oxymorphone O attached at C-14 O

O -- O O

HCN OH

1,4- carbonate oxymorphone O tetrahydronaphthalene attached at C-3 O O NCH

OH O

O

1,4- carbonate oxymorphone O tetrahydronaphthalene attached at C-14 O

O -- O O

HCN OH diphenylcyclohexanol Sulphonate oxymorphone attached at C-3 O-S- O NCH

OH O

O US 2011/0077222 A1 Mar. 31, 2011 11

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure diphenylcyclohexanol Sulphonate oxymorphone O attached at C-14 O O O-S- O

HCN 3 OH phenylhexanol Sulphonate oxymorphone O attached at

OH O

O phenylhexanol Sulphonate oxymorphone O attached at C-14 O O O-S- O

HCN OH biphenylpropanol Sulphonate oxymorphone attached at O C-3 OHS- O NCH

OH O

O biphenylpropanol Sulphonate oxymorphone O attached at C-14 O O O-S-O

HCN OH US 2011/0077222 A1 Mar. 31, 2011 12

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- Sulphonate oxymorphone O tetrahydronaphthalene attached at C-3 O-S- O NCH

OH O

O

1,4- Sulphonate oxymorphone O tetrahydronaphthalene attached at C-14 O O O-S- O

HCN OH

diphenylcyclohexanol phosphate oxycodone O diester

O O O- – O HO HCN O-CH

phenylhexanol phosphate oxycodone O diester

O | O O- - O

HO HCN O-CH biphenylpropanol phosphate oxycodone O diester

O O O- – O HO HCN O-CH US 2011/0077222 A1 Mar. 31, 2011 13

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- phosphate oxycodone O tetrahydronaphthalene diester

O | O O- - O

HO HCN O-CH

diphenylcyclohexanol carbonate oxycodone O

O

O -- O O

HCN O-CH

phenylhexanol carbonate oxycodone O

O

O -- O O

HCN O-CH

biphenylpropanol carbonate oxycodone O

O

O -- O O

HCN O-CH

1,4- carbonate oxycodone O tetrahydronaphthalene

O

O -- O O

HCN O-CH US 2011/0077222 A1 Mar. 31, 2011 14

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure diphenylcyclohexanol Sulphonate oxycodone O

O O O-S- O

HCN O-CH

phenylhexanol Sulphonate oxycodone O

O O O-S- O

HCN O-CH biphenylpropanol Sulphonate oxycodone O

O O O-S- O

HCN O-CH

1,4- Sulphonate oxycodone O tetrahydronaphthalene

O | O COr OHS- O HCN O-CH diphenylcyclohexanol phosphate codeine diester V O

O

O

O-P-O NCH HO US 2011/0077222 A1 Mar. 31, 2011 15

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol phosphate codeine HC diester V O

O

O-P-O NCH HO biphenylpropanol phosphate codeine HC diester V O

O

O-P-O NCH HO

1,4- phosphate codeine HC tetrahydronaphthalene diester Y O ( )

O-P-O NCH HO

diphenylcyclohexanol carbonate codeine HC V O

O

O o-l-o NCH US 2011/0077222 A1 Mar. 31, 2011 16

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol carbonate codeine H3C V O

O

O O -- O NCH

biphenylpropanol carbonate codeine H3C V O

O

O O -- O NCH tetrahydronaphthalene1,4- carbonate codeine HCY O ( ) O O -- O NCH

CH4 diphenylcyclohexanol Sulphonate codeine H3C V O

O

O

O-S- O NCH US 2011/0077222 A1 Mar. 31, 2011 17

TABLE I-continued Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol Sulphonate codeine HC V O

O

O

O-S-O NCH biphenylpropanol Sulphonate codeine HC V O

O

O

O-S-O NCH

1,4- Sulphonate codeine HC tetrahydronaphthalene V O

O

O

O-S-O NCH diphenylcyclohexanol phosphate naltrexone diester attached at O C-3 - 7 N O–o O H Xo O

O diphenylcyclohexanol phosphate naltrexone O diester attached at C-14 O O

o--oHO N X. OH US 2011/0077222 A1 Mar. 31, 2011 18

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol phosphate naltrexone O diester attached at O-P-O N C-3 HO OH O

O phenylhexanol phosphate naltrexone O diester attached at C-14 O O

o--oHO N f OH biphenylpropanol phosphate naltrexone diester O attached at C-3 | o--o N HO OH O

O biphenylpropanol phosphate naltrexone O diester attached at C-14 O O

o--oHO N OH

1,4- phosphate naltrexone O tetrahydronaphthalene diester attached at O-P-O N C-3 HO OH O

O US 2011/0077222 A1 Mar. 31, 2011 19

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- phosphate naltrexone O tetrahydronaphthalene diester attached at C-14 O O

o--oHO N OH

diphenylcyclohexanol carbonate naltrexone attached at C-3

diphenylcyclohexanol carbonate naltrexone attached at C-14

phenylhexanol carbonate naltrexone attached at C-3

phenylhexanol carbonate naltrexone attached at C-14 US 2011/0077222 A1 Mar. 31, 2011 20

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure biphenylpropanol carbonate naltrexone attached at C-3

biphenylpropanol carbonate naltrexone attached at C-14

OH

1,4- carbonate naltrexone tetrahydronaphthalene attached at C-3

1,4- carbonate naltrexone tetrahydronaphthalene attached at C-14

diphenylcyclohexanol Sulphonate naltrexone attached at C-3 US 2011/0077222 A1 Mar. 31, 2011 21

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure diphenylcyclohexanol Sulphonate naltrexone O attached at C-14 O O O-S- O A phenylhexanol Sulphonate naltrexone O attached at | Q C-3 O-S-O N

OH O

O phenylhexanol Sulphonate naltrexone O attached at C-14 O O O-S-O

N f OH biphenylpropanol Sulphonate naltrexone attached at O C-3 O-S- O N

O H O

O biphenylpropanol Sulphonate naltrexone O attached at C-14 O O O-S-O

N I OH US 2011/0077222 A1 Mar. 31, 2011 22

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- Sulphonate naltrexone O tetrahydronaphthalene attached at C-3 O-S-O N

OH O

O

1,4- Sulphonate naltrexone O tetrahydronaphthalene attached at C-14 O O O-S-O

N f OH diphenylcyclohexanol phosphate morphine diester attached at C-3

diphenylcyclohexanol phosphate morphine HO diester attached at C-6 O

O-P-O N-CH HO phenylhexanol phosphatediester morphine O y H. attached at O-P-O N C-3 HO

O

HO US 2011/0077222 A1 Mar. 31, 2011 23

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol phosphate morphine HO diester attached at C-6 O

O

O-P-O N-CH HO biphenylpropanol phosphate morphine diester O attached at C-3 | y H. o--o N HO s() HO biphenylpropanol phosphate morphine HO diester attached at C-6 -( ) O

O-P-O N-CH HO

1,4- phosphate morphine O tetrahydronaphthalene diester attached at y H. C-3 O- –o N COr HO O

HO

1,4- phosphate morphine HO tetrahydronaphthalene diester attached at C-6 O

O

N-CH COr HO US 2011/0077222 A1 Mar. 31, 2011 24

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure diphenylcyclohexanol carbonate morphine attached at O C-3 H. O -- O N

O

HO diphenylcyclohexanol carbonate morphine HO attached at C-6

O

O O -- O N-CH

phenylhexanol carbonate morphine O CH attached at W 3 C-3 O O N O ( )

HO phenylhexanol carbonate morphine HO attached at C-6 O ( ) O O -- O biphenylpropanol carbonate morphine attached at O C-3 O -- O H.

O

HO US 2011/0077222 A1 Mar. 31, 2011

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure biphenylpropanol carbonate morphine HO attached at C-6

O

O o--o N-CH

1,4- carbonate morphine O CH tetrahydronaphthalene attached at M 3 C-3 O O N O ( )

HO

1,4- carbonate morphine HO tetrahydronaphthalene attached at C-6 O ( ) O o-l-o N-CH diphenylcyclohexanol Sulphonate morphine attached at C-3 H. O-S- O N

O

HO diphenylcyclohexanol Sulphonate morphine HO attached at C-6

O

O

O-S-O N-CH US 2011/0077222 A1 Mar. 31, 2011 26

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol Sulphonate morphine O attached at MCH3 C-3 O-S- O N

O

HO phenylhexanol Sulphonate morphine HO attached at C-6

O

O-S- O N-CH biphenylpropanol Sulphonate morphine attached at O C-3 | H. OHS- O N O ( )

HO biphenylpropanol Sulphonate morphine HO attached at C-6 O ( )

O-S-O N-CH

1,4- Sulphonate morphine O CH tetrahydronaphthalene attached at A 3 C-3 O-S-O N

O

HO US 2011/0077222 A1 Mar. 31, 2011 27

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- Sulphonate morphine HO tetrahydronaphthalene attached at C-6

O

O-S-O N-CH diphenylcyclohexanol phosphate buprenorphine diester attached at C-3

diphenylcyclohexanol phosphate buprenorphine diester attached at C-6

phenylhexanol phosphate buprenorphine diester attached at C-3 US 2011/0077222 A1 Mar. 31, 2011 28

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol phosphate buprenorphine diester attached at C-6

biphenylpropanol phosphate buprenorphine diester attached at C-3

biphenylpropanol phosphate buprenorphine diester attached at C-6

1,4- phosphate buprenorphine tetrahydronaphthalene diester attached at C-3 US 2011/0077222 A1 Mar. 31, 2011 29

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- phosphate buprenorphine tetrahydronaphthalene diester attached at C-6

diphenylcyclohexanol carbonate buprenorphine attached at C-3

diphenylcyclohexanol carbonate buprenorphine attached at C-6

phenylhexanol carbonate buprenorphine attached at C-3

OH

CH US 2011/0077222 A1 Mar. 31, 2011 30

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

phenylhexanol carbonate buprenorphine attached at C-6

biphenylpropanol carbonate buprenorphine attached at C-3

biphenylpropanol carbonate buprenorphine attached at C-6

1,4- carbonate buprenorphine tetrahydronaphthalene attached at C-3

O OH US 2011/0077222 A1 Mar. 31, 2011 31

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure

1,4- carbonate buprenorphine tetrahydronaphthalene attached at C-6

diphenylcyclohexanol Sulphonate buprenorphine attached at C-3

diphenylcyclohexanol Sulphonate buprenorphine attached at C-6

phenylhexanol Sulphonate buprenorphine attached at C-3 US 2011/0077222 A1 Mar. 31, 2011 32

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure phenylhexanol Sulphonate buprenorphine attached at C-6

biphenylpropanol Sulphonate buprenorphine attached at C-3

biphenylpropanol Sulphonate buprenorphine attached at C-6

1,4- Sulphonate buprenorphine tetrahydronaphthalene attached at C-3 US 2011/0077222 A1 Mar. 31, 2011 33

TABLE I-continued

Exemplary Embodiments of Sustained-Release Opiate Compositions

Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure 1,4- Sulphonate buprenorphine tetrahydronaphthalene attached at C-6

diphenylcyclohexanol phosphate oxycodone O triester

O

O O o-CH3 W O-P \ HCN O O HCN

O

O N CH diphenylcyclohexanol phosphate oxycodone triester maltrexone

N

OH

O OK

O O O

HCN

O

O N CH3 US 2011/0077222 A1 Mar. 31, 2011 34

TABLE I-continued

Exempl Embodiments of Sustained-Release Opiate Compositions Blood Albumin Connecting Binder (A) Bridge (B) Opiate (X) Chemical Structure diphenylcyclohexanol Succinate (-)naltrexone diester

diphenylcyclohexanol Succinate (+)naltrexone diester

EXAMPLES ance of the codeine and codeine 4,4-diphenylcyclohexyl phosphate may be statistically compared using a non-paired, 0069. The following example illustrates various aspects of two-tailed T-test. The terminal half life of the codeine 4.4- the invention. diphenylcyclohexyl phosphate may be determined to be sig nificantly greater than the codeine composition, and the clear Example 1 ance of the codeine 4,4-diphenylcyclohexyl phosphate may Pharmacokinetic Assessment of Stabilized Opiate be determined to be significantly smaller than the codeine Composition composition at each sample time. These findings may indi cate that the modification of codeine to codeine 4,4-diphenyl 0070. To assess the pharmacokinetics of a sustained-re cyclohexyl phosphate may result in a more Sustained release lease opiate composition compared to the non-modified opi form of codeine compared to unmodified codeine. ate, the following experiment may be conducted. Heparinized 0072 Having described the invention in detail, it will be blood samples may be collected from a population of con apparent that modifications and variations are possible. Those scious rats (n-6) prior to the intravenous administration of of skill in the art should, in light of the present disclosure, codeine at a dose of 10 mg/kg to 50% of the rats (n-3) or appreciate that many changes could be made in the specific codeine 4,4-diphenylcyclohexyl phosphate at a dose of 10 embodiments that are disclosed and still obtain a like or mg/kg to the other 50% of the rats (n=3). Heparinized blood similar result without departing from the spirit and scope of samples may be collected via the femoral artery of all con the invention, therefore all matter set forth is to be interpreted scious rats at time intervals of 5 minutes, 30 minutes, 1 hour, as illustrative and not in a limiting sense. 2 hours, 4 hours, 6 hours, 10 hours and 24 hours after the initial administration of the codeine compositions. All hep What is claimed is: arinized blood samples may be centrifuged after collection, 1. A Sustained-release opiate composition comprising: and the resulting plasma may be collected and frozen. a. an opiate; 0071 All frozen plasma samples, as well as frozen b. a non-peptide blood albumin binder; and, samples of the codeine and codeine 4,4-diphenylcyclohexyl c. a connecting bridge attached to the opiate and to the phosphate compositions administered to the rats, may be non-peptide blood albumin binder. analyzed to determine the presence and concentrations of 2. The composition of claim 1, wherein the opiate is chosen codeine in both free and bound forms. The measured plasma from adulmine, allocryptopine, aporphine, benzylmorphine, concentrations may be evaluated using a non-compartmental berberine, bicuculine, bicucine, bulbocapnine, buprenor analysis method performed using existing analysis Software phine, butorphanol, canadine, capaurine, chellerythrine, che (WinNonLin, Pharsight, St. Louis, Mo.) to determine termi lidonine, codamine, codeine, , coreximine, corlu nal half lives and clearances. The terminal half life and clear mine, corybulbine, cory cavamine, corycavine, corydaline, US 2011/0077222 A1 Mar. 31, 2011 corydine, corytuberine, cularine, cotarnine, cryptopine, diacetylmorphine, dicentrine, dihydrosanguinarine, dipro cycloartenol, cycloartenone, cyclolaudenol, dehydroreticu panoylmorphine, epiporphyroxine, ethylmorphine, eupaver line, desomorphine, dextropropoxyphene, dextrorphanol, ine, fagarine, fentanyl, glaucine, homochelidonoine, hydroc diacetylmorphine, dicentrine, dihydrosanguinarine, dipro odone, hydrocotarnine, hydromorphone, hydroxythebaine, panoylmorphine, epiporphyroxine, ethylmorphine, eupaver isoboldine, isocorybulbine, isocorydine, isocorypalmine, ine, fagarine, fentanyl, glaucine, homochelidonoine, hydroc isoquinoline, laudanidine, laudanine, laudanosine, levorpha odone, hydrocotarnine, hydromorphone, hydroxythebaine, nol, magnoflorine, meconic acid, methadone, morphine, nal isoboldine, isocorybulbine, isocorydine, isocorypalmine, buphine, nalmefene, naloxone, naltrexamine, C.-naltrexol. isoquinoline, laudanidine, laudanine, laudanosine, levorpha B-maltrexol, naltrexone, naphthaphenanthridine, narceline, nol, magnoflorine, meconic acid, methadone, morphine, nal narceinone, narcotoline, narcotine, neopine, nicomorphine, buphine, nalmefene, naloxone, naltrexamine, C.-naltrexol. norlaudanosoline, norsanguinarine, noscapine, opium, oripa B-maltrexol, naltrexone, naphthaphenanthridine, narceline, vine, oxycodone, oxymorphone, oxysanguinarine, palau narceinone, narcotoline, narcotine, neopine, nicomorphine, dine, papaverine, papaveraldine, papaverrubine, perparin, norlaudanosoline, norsanguinarine, noscapine, opium, oripa pethidine, , phtalide-isoquinoline, porphyroX vine, oxycodone, oxymorphone, oxysanguinarine, palau ine, protopine, pseudocodeine, pseudomorphine, reticuline, dine, papaverine, papaveraldine, papaverrubine, perparin, salutaridine, sinoacutine, sanguinarine, Scoulerine, som pethidine, phenanthrene, phtalide-isoquinoline, porphyroX niferine, , tapentadol, tetrahydroprotoberberine, ine, protopine, pseudocodeine, pseudomorphine, reticuline, thebaine, tramadol, and Xanthaline. salutaridine, sinoacutine, sanguinarine, Scoulerine, Som 10. The composition of claim 8, wherein the first non niferine, Stepholidine, tapentadol, tetrahydroprotoberberine, peptide blood albumin binder and the second non-peptide thebaine, tramadol, and Xanthaline. blood albuminbinder are essentially the same substance cho 3. The composition of claim 1, wherein the non-peptide Sen from diphenylcyclohexanol, phenylhexanol, and biphe blood albumin binder comprises one or more functional nylpropanol. groups chosen from aliphatic and aryl groups, wherein the 11. The composition of claim 8, wherein the first connect aliphatic and aryl groups comprise between about 1 and 60 ing bridge and the second connecting bridge comprise differ carbons and any one or more Substituents chosen from a ent Substances chosen from phosphate diester, carbonate, and nitrogen, an oxygen, a Sulfur, a halogen, an alkyl group, an Sulphonate. amide, an ester, and a sulfonamide. 12. The composition of claim 8, wherein the first connect 4. The composition of claim 1, wherein the connecting ing bridge and the second connecting bridge are cleaved at bridge comprises one or more functional groups chosen from different times after administration of the composition. phosphate diester, carbonate, and Sulphonate. 13. The composition of claim 8, wherein the composition 5. The composition of claim 1, wherein: further comprises a third compound comprising a third opi a. the opiate is chosen from oxycodone, oxymorphone, ate, a third non-peptide blood albumin binder and a third hydrocodone, hydromorphone, buprenorphine, nalox connecting bridge attached to the third opiate and to the third one, and naltrexone; non-peptide blood albuminbinder, wherein the third connect b. the non-peptide blood albumin binder is chosen from ing bridge is a different Substance from the first connecting diphenylcyclohexanol, phenylhexanol, and biphenyl bridge and the second connecting bridge, and wherein the propanol; and, third connecting bridge is selected from phosphate diester, c. the connecting bridge is a phosphate diester. carbonate, and Sulphonate. 6. The composition of claim 5, wherein the non-peptide 14. A Sustained-release opiate composition comprising: blood albumin binder is diphenylcyclohexanol. a. a first opiate; 7. The composition of claim 1, wherein the composition b. a second opiate; further comprises a second opiate attached to the connecting c. a non-peptide blood albumin binder, and, bridge. d. a first connecting bridge attached to the first opiate, to the 8. A Sustained-release opiate composition comprising: second opiate, and to the non-peptide blood albumin a. a first compound comprising a first opiate, a first non binder. peptide blood albumin binder, and a first connecting 15. The composition of claim 14, wherein the first opiate is bridge attached to the first opiate and to the first non essentially the same Substance as the second opiate, and peptide blood albumin binder; and, wherein the first opiate and the second opiate are chosen from b. a second compound comprising a second opiate, a sec adulmine, allocryptopine, aporphine, benzylmorphine, ber ond non-peptide blood albumin binder, and a second berine, bicuculine, bicucine, bulbocapnine, buprenorphine, connecting bridge attached to the second opiate and to butorphanol, canadine, capaurine, chellerythrine, chelido the second non-peptide blood albumin binder. nine, codamine, codeine, coptisine, coreximine, corlumine, 9. The composition of claim 8, wherein the first opiate is corybulbine, corycavamine, corycavine, corydaline, cory essentially the same Substance as the second opiate, and dine, cory tuberine, cularine, cotarnine, cryptopine, wherein the first opiate and the second opiate are chosen from cycloartenol, cycloartenone, cyclolaudenol, dehydroreticu adulmine, allocryptopine, aporphine, benzylmorphine, ber line, desomorphine, dextropropoxyphene, dextrorphanol, berine, bicuculine, bicucine, bulbocapnine, buprenorphine, diacetylmorphine, dicentrine, dihydrosanguinarine, dipro butorphanol, canadine, capaurine, chellerythrine, chelido panoylmorphine, epiporphyroxine, ethylmorphine, eupaver nine, codamine, codeine, coptisine, coreximine, corlumine, ine, fagarine, fentanyl, glaucine, homochelidonoine, hydroc corybulbine, cory cavamine, cory cavine, corydaline, cory odone, hydrocotarnine, hydromorphone, hydroxythebaine, dine, cory tuberine, cularine, cotarnine, cryptopine, isoboldine, isocorybulbine, isocorydine, isocorypalmine, cycloartenol, cycloartenone, cyclolaudenol, dehydroreticu isoquinoline, laudanidine, laudanine, laudanosine, levorpha line, desomorphine, dextropropoxyphene, dextrorphanol, nol, magnoflorine, meconic acid, methadone, morphine, nal US 2011/0077222 A1 Mar. 31, 2011 36 buphine, nalmefene, naloxone, naltrexamine, C.-naltrexol. 18. The composition of claim 14, wherein: B-maltrexol, naltrexone, naphthaphenanthridine, narceline, a. the first opiate is selected from oxycodone, oxymor narceinone, narcotoline, narcotine, neopine, nicomorphine, phone, hydrocodone, hydromorphone, buprenorphine, norlaudanosoline, norsanguinarine, noscapine, opium, oripa vine, oxycodone, oxymorphone, oxysanguinarine, palau naloxone, and naltrexone; dine, papaverine, papaveraldine, papaverrubine, perparin, b. the second opiate is essentially the same Substance as the pethidine, phenanthrene, phtalide-isoquinoline, porphyroX first opiate; ine, protopine, pseudocodeine, pseudomorphine, reticuline, c. the non-peptide blood albumin binder is selected from salutaridine, sinoacutine, sanguinarine, Scoulerine, Som diphenylcyclohexanol, phenylhexanol, and biphenyl niferine, Stepholidine, tapentadol, tetrahydroprotoberberine, propanol; and, thebaine, tramadol, and Xanthaline. d. the connecting bridge is a phosphate diester. 16. The composition of claim 14, wherein the non-peptide 19. The composition of claim 14, wherein the non-peptide blood albumin binder comprises one or more functional blood albumin binder is diphenylcyclohexanol and the con groups chosen from aliphatic or aryl groups, wherein the necting bridge is phosphate diester. aliphatic or aryl groups comprise between about 1 and 60 20. The composition of claim 14, wherein the composition carbons and any one or more Substituents chosen from a is administered at a dosage equal to or greater than a dosage nitrogen, an oxygen, a Sulfur, a halogen, an alkyl group, an recommended for the corresponding opiate administered amide, an ester, and a sulfonamide. without the non-peptide blood albumin binder and the con 17. The composition of claim 14, wherein the connecting necting bridge. bridge comprises one or more functional groups chosen from phosphate diester, carbonate, and Sulphonate.