CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 12/728,622, filed Mar. 22, 2010, which is a divisional of U.S. patent application Ser. No. 11/143,535, filed Jun. 2, 2005, now U.S. Pat. No. 7,700,626, issued Apr. 20, 2010, which claims benefit under 35 USC 119(e) of U.S. Provisional Application No. 60/576,939, filed Jun. 4, 2004. The disclosures of each of the above-identified applications are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compositions containing opioid antagonists. More particularly, the present invention relates to compositions containing opioid antagonists, injectable dosage formulations, kits, and methods of preparing and using same.

BACKGROUND OF THE INVENTION

Oral dosage forms, such as tablets and capsules, of pharmaceuticals are widely used dosage forms. However, certain patients are unable to tolerate oral dosage forms due to their inability to swallow the tablet or capsule, due to age, infirmity, or lack of consciousness. Thus, it would be desirable to be able to administer the pharmaceutical via a parenteral route, such as intravenous, intramuscular, or subcutaneous injection. Formulating solid pharmaceuticals for administration via parenteral routes can be problematic, however, because of the frequent difficulty of solubilizing the solid active ingredient in a pharmaceutically acceptable liquid solvent.

The low solubility problem has been addressed in the following ways:

1. Solubilizing surfactants may be used to increase the solubility of the active ingredient in the solvent. Unfortunately, the solubilizing surfactants may cause anaphylactic reactions in susceptible patients.
2. Oil-in-water emulsions may be used but such formulations suffer from a number of drawbacks, including pain at the injection site, poor physical stability, potential for embolisms, and the need for strict aseptic handling.
3. Complexing the active ingredients with amphipathic agents that increase their solubility (such as Î²-cyclodextrin) may be used, but these suffer limitations including higher cost and their currently limited acceptance by regulatory agencies for use in human pharmaceutical products.

[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]acetic acid dihydrate (USAN name alvimopan) and its active metabolite are peripherally-acting Î¼ opioid antagonists that may be used in the treatment of postoperative ileus, postpartum ileus, pruritis, constipation, opioid bowel dysfunction, urinary retention, biliary spasm, opioid bowel dysfunction, colic, postoperative nausea, and/or postoperative vomiting as well as other indications. Alvimopan is currently available in solid dosage form. However, it would be desirable to provide the active ingredient in an injectable form to avoid the problems with swallowing tablets or capsules or in administering to patients who are undergoing surgery and not conscious. Alvimopan and its active metabolite are 3,4-disubstituted-4-aryl piperidines that are zwitterions. They have extremely low solubility in water and many common pharmaceutically acceptable solvents.

What would be desirable are injectable dosage formulations of alvimopan and related 4-aryl substituted piperidine compounds that are zwitterionic in nature. The present invention is directed to these and other important objectives.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to methods, comprising the steps of:

a. providing a composition, comprising:

- (i) a pharmaceutically-acceptable metal salt of at least one compound of formula I:

[Image Omitted]

- - wherein:
  - R¹is hydrogen or alkyl;
  - R²is hydrogen, alkyl or alkenyl;
  - R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aralkyl;
  - R⁴is hydrogen, alkyl or alkenyl;
  - A is OR^Sor NR⁶R⁷;
  - R⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R⁶is hydrogen or alkyl;
  - R⁷is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R⁶and R⁷form a heterocyclic ring;
  - B is

[Image Omitted]

- C(â• O)W or NR⁸R⁹;
  - R⁸is hydrogen or alkyl;
  - R⁹is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aralkyl or, together with the nitrogen atom to which they are attached, R⁸and R⁹form a heterocyclic ring;
  - W is OR¹⁰, IN¹¹R¹², or OE;
  - R¹⁰is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R¹¹is hydrogen or alkyl;
  - R¹²is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl or alkylene substituted C(â• O)Y or, together with the nitrogen atom to which they are attached, R¹¹and R¹²form a heterocyclic ring;
  - E is

[Image Omitted]

- alkylene substituted (Câ• O)D, or â€”R¹³OC(â• O)R¹⁴;
  - R¹³is alkyl substituted alkylene;
  - R¹⁴is alkyl;
  - D is OR¹⁵or NR¹⁶R¹⁷;
  - R¹⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R¹⁶is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
  - R¹⁷is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R¹⁶and R¹⁷form a heterocyclic ring;
  - Y is OR¹⁸or NR¹⁹R²⁰;
  - R¹⁸is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R¹⁹is hydrogen or alkyl;
  - R²⁰is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl or, together with the nitrogen atom to which they are attached, R¹⁹and R²⁰form a heterocyclic ring;
  - R²¹is hydrogen or alkyl; and
  - n is 0 to 4;
- (ii) at least one bulking agent that crystallizes;
- (iii) at least one weak base; and
- (iv) water;
  - wherein said composition has an initial pH of at least about 10.5; and
    b. adjusting the pH of said composition to a final pH in the range of about 9 to about 11;

wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration.

In another embodiment, the invention is directed, in part, to methods, further comprising the step of drying said composition to remove at least a portion of said water to form a partially or fully dried product.

In yet other embodiments, the invention is directed to methods further comprising the step of reconstituting said dried product by combining therewith a pharmaceutically acceptable solvent to form a solution of said dried product.

In other embodiments, the invention is directed to the products produced by each of the above-described methods.

In further embodiments, the invention is directed to methods of further comprising the step of administering said solution of said dried product to a patient.

In yet further embodiments, the invention is directed to compositions, comprising:

a. a pharmaceutically-acceptable metal salt of at least one compound of formula I:

[Image Omitted]

- wherein:
- R¹is hydrogen or alkyl;
- R²is hydrogen, alkyl, or alkenyl;
- R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R⁴is hydrogen, alkyl, or alkenyl;
- A is OR⁵or NR⁶R⁷;
- R⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R⁶is hydrogen or alkyl;
- R⁷is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R⁶and R⁷form a heterocyclic ring;
- B is

[Image Omitted]

- C(â• O)W or NR⁸R⁹;
- R⁸is hydrogen or alkyl;
- R⁹is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aralkyl or, together with the nitrogen atom to which they are attached, R⁸and R⁹form a heterocyclic ring;
- W is OR¹⁰, NR¹¹R¹², or OE;
- R¹⁰is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R¹¹is hydrogen or alkyl;
- R¹²is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl or alkylene substituted C(â• O)Y or, together with the nitrogen atom to which they are attached, R¹¹and R¹²form a heterocyclic ring;
- E is

[Image Omitted]

alkylene substituted (Câ• O)D, or â€”R¹³OC(â• O)R¹⁴;

- R¹³is alkyl-substituted alkylene;
- R¹⁴is alkyl;
- D is OR¹⁵or NR'6Râ€²7;
- R¹⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R¹⁶is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, or cycloalkenyl-substituted alkyl;
- R¹⁷is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R¹⁶and R¹⁷form a heterocyclic ring;
- Y is OR¹⁸or NR¹⁹R²⁰;
- R¹⁸is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R¹⁹is hydrogen or alkyl;
- R²⁰is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl or, together with the nitrogen atom to which they are attached, R¹⁹and R²⁰form a heterocyclic ring;
- R²¹is hydrogen or alkyl; and
- n is 0 to 4;
  b. at least one bulking agent that crystallizes;

wherein said composition has a density of less than about 1.0 g/cm³;

wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration.

In other embodiments, the invention is directed to compositions, comprising:

a. a pharmaceutically-acceptable metal salt of at least one compound of formula I:

[Image Omitted]

- wherein:
- R¹is hydrogen or alkyl;
- R²is hydrogen, alkyl or alkenyl;
- R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aralkyl;
- R⁴is hydrogen, alkyl or alkenyl;
- A is OR^Sor NR⁶R⁷;
- R⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R⁶is hydrogen or alkyl;
- R⁷is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R⁶and R⁷form a heterocyclic ring;
- B is

[Image Omitted]

- C(â• O)W or NR⁸R⁹;
- R⁸is hydrogen or alkyl;
- R⁹is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl, or aralkyl or, together with the nitrogen atom to which they are attached, R⁸and R⁹form a heterocyclic ring;
- W is OR¹⁰, NR¹¹R¹², or OE;
- R¹⁰is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R¹¹is hydrogen or alkyl;
- R¹²is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl or alkylene substituted C(â• O)Y or, together with the nitrogen atom to which they are attached, R¹¹and R¹²form a heterocyclic ring;
- E is

[Image Omitted]

alkylene-substituted (Câ• O)D, or â€”R¹³OC(â• O)R¹⁴;

- R¹³is alkyl-substituted alkylene;
- R¹⁴is alkyl;
- D is OR¹⁵or NR¹⁶R¹⁷;
- R¹⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R¹⁶is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, or cycloalkenyl-substituted alkyl;
- R¹⁷is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R¹⁶and R¹⁷form a heterocyclic ring;
- Y is OR¹⁸or NR¹⁹R²⁰;
- R¹⁸is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
- R¹⁹is hydrogen or alkyl;
- R²⁰is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl or, together with the nitrogen atom to which they are attached, R¹⁹and R²⁰form a heterocyclic ring;
- R²¹is hydrogen or alkyl; and
- n is 0 to 4;
b. at least one bulking agent that crystallizes;
c. less than about 1% by weight, based on the total weight of the composition, of a solubilizing surfactant;
d. less than about 10% by weight, based on the total weight of the composition, of a non-aqueous solvent; and
e. less than about 500% by weight, based on the total weight of the composition, of cyclodextrin;

wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration.

In yet another embodiment, the invention is directed to injectable dosage formulations, comprising the above-described compositions:

In yet other embodiments, the invention is directed to kits, comprising:

a. a container comprising an injectable dosage formulation; and
b. instructions for preparing an injectable solution.

In yet other embodiments, the invention is directed to methods of preventing or treating a side effect associated with an opioid in a patient, comprising the step of:

administering to said patient in need thereof an effective amount of the above-described composition.

The methods are useful in the prevention and treatment of ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea, or vomiting or combinations thereof, particularly postoperative ileus, postpartum ileus, opioid bowel dysfunction, postoperative nausea, or postoperative vomiting or combinations thereof.

In other embodiments, the invention is directed to methods of preventing or treating pain in a patient, comprising the step of:

administering to said patient in need thereof an effective amount of the above-described composition.

In preferred embodiments, the composition further comprises at least one opioid.

These and other aspects of the invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As employed above and throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

As used herein, â€œcomposition having improved solubility and bioavailability for oral or parenteral administrationâ€ refers to a composition containing at least one opioid antagonist suitable for oral or parenteral administration that has a higher level of solubility and bioavailability relative to a composition prepared from the same active ingredient(s) and bulking agent(s) but having different final physical properties (such as density) due to the process by which the composition was formed, preferably minimizing or eliminating the inclusion of undesirable components, such as solubilizing surfactants, non-aqueous solvents, cyclodextrin, and the like used in the prior art to improve the solubility of the active ingredient.

As used herein, â€œparenteral administrationâ€ refers to the administration of a drug to a patient outside of the intestine and not by way of the alimentary tract. The primary routes of parenteral administration to a mammalian host are intravenous, intramuscular, subcutaneous, intradermal, intraocular, intrasynovial, intracardiac, intraspinal, intra-articular, intrathecal, intra-arterial, transepithelial including transdermal, intraperitoneal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, nasal inhalation via insufflation, aerosol and rectal systemic. The preferred parenteral routes of administration are intravenous, intramuscular, and subcutaneous via injection.

As used herein, â€œbioavailabilityâ€ refers to the rate and extent to which a drug or other substance becomes available to the target tissue after administration. In the context of this invention, bioavailability refers to the degree to which the opioid antagonist becomes available to the opioid receptors in the central nervous system or peripheral thereto.

As used herein, â€œalkylâ€ refers to an optionally substituted, saturated straight, branched, or cyclic hydrocarbon having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 1 to about 8 carbon atoms, herein referred to as â€œlower alkylâ€ , being preferred. â€œBranchedâ€ refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. In certain preferred embodiments, the alkyl group is a C₁-C₅alkyl group, i.e., a branched or linear alkyl group having from 1 to about 5 carbons. In other preferred embodiments, the alkyl group is a C₁-C₃alkyl group, i.e., a branched or linear alkyl group having from 1 to about 3 carbons. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. â€œLower alkylâ€ refers to an alkyl group having 1 to about 6 carbon atoms. Preferred alkyl groups include the lower alkyl groups of 1 to about 3 carbons. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl, adamantyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

As used herein, â€œalkyleneâ€ refers to a bivalent alkyl radical having the general formula â€”(CH₂)_nâ€”, where n is 1 to 10, and all combinations and subcombinations of ranges therein. The alkylene group may be straight, branched or cyclic. Non-limiting examples include methylene, methylene (â€”CH₂â€”), ethylene (â€”CH₂CH₂â€”), propylene (â€”(CH₂)₃â€”), trimethylene, pentamethylene, and hexamethylene. There may be optionally inserted along the alkylene group one or more oxygen, sulfur or optionally substituted nitrogen atoms, wherein the nitrogen substituent is alkyl as described previously. Alkylene groups can be optionally substituted. The term â€œlower alkyleneâ€ herein refers to those alkylene groups having from about 1 to about 6 carbon atoms. Preferred alkylene groups have from about 1 to about 4 carbons.

As used herein, â€œalkenylâ€ refers to a monovalent alkyl radical containing at least one carbon-carbon double bond and having from 2 to about 10 carbon atoms in the chain, and all combinations and subcombinations of ranges therein. Alkenyl groups can be optionally substituted. In certain preferred embodiments, the alkenyl group is a C₂-C₁₀alkyl group, i.e., a branched or linear alkenyl group having from 2 to about 10 carbons. In other preferred embodiments, the alkenyl group is a C₂-C₆alkenyl group, i.e., a branched or linear alkenyl group having from 2 to about 6 carbons. In still other preferred embodiments, the alkenyl group is a C₃-C₁₀alkenyl group, i.e., a branched or linear alkenyl group having from about 3 to about 10 carbons. In yet other preferred embodiments, the alkenyl group is a C₂-C₅alkenyl group, i.e., a branched or linear alkenyl group having from 2 to about 5 carbons. Exemplary alkenyl groups include, for example, vinyl, propenyl, butenyl, pentenyl hexenyl, heptenyl, octenyl, nonenyl and decenyl groups.

As used herein, â€œarylâ€ refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system having from about 5 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 10 carbons being preferred. Non-limiting examples include, for example, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

As used herein, â€œaralkylâ€ refers to alkyl radicals bearing an aryl substituent and have from about 6 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 10 carbon atoms being preferred. Aralkyl groups can be optionally substituted in either the aryl or alkyl portions. Non-limiting examples include, for example, phenylmethyl (benzyl), diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl and 3-(4-methylphenyl)propyl.

As used herein, â€œheteroarylâ€ refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aromatic ring system that includes at least one, and preferably from 1 to about 4 sulfur, oxygen, or nitrogen heteroatom ring members. Heteroaryl groups can have, for example, from about 3 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 4 to about 10 carbons being preferred. Non-limiting examples of heteroaryl groups include, for example, pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

As used herein, â€œcycloalkylâ€ refers to an optionally substituted, alkyl group having one or more rings in their structures having from about 3 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 3 to about 10 carbon atoms being preferred, with from about 3 to about 8 carbon atoms being more preferred, with from about 3 to about 6 carbon atoms being even more preferred. Multi-ring structures may be bridged or fused ring structures. The cycloalkyl group may be optionally substituted with, for example, alkyl, preferably C₁-C₃alkyl, alkoxy, preferably C₁-C₃alkoxy, or halo. Non-limiting examples include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl, and adamantyl.

As used herein, â€œcycloalkyl-substituted alkylâ€ refers to a linear alkyl group, preferably a lower alkyl group, substituted at a terminal carbon with a cycloalkyl group, preferably a C₃-C₈cycloalkyl group. Non-limiting examples include, for example, cyclohexylmethyl, cyclohexylethyl, cyclopentylethyl, cyclopentylpropyl, cyclopropylmethyl, and the like.

As used herein, â€œcycloalkenylâ€ refers to an olefinically unsaturated cycloalkyl group having from about 4 to about 10 carbons, and all combinations and subcombinations of ranges therein. In preferred embodiments, the cycloalkenyl group is a C₅-C₈cycloalkenyl group, i.e., a cycloalkenyl group having from about 5 to about 8 carbons.

As used herein, â€œalkylcycloalkylâ€ refers to an optionally substituted ring system comprising a cycloalkyl group having one or more alkyl substituents. Non-limiting examples include, for example, alkylcycloalkyl groups include 2-methylcyclohexyl, 3,3-dimethylcyclopentyl, trans-2,3-dimethylcyclooctyl, and 4-methyldecahydronaphthalenyl.

As used herein, â€œheteroaralkylâ€ refers to an optionally substituted, heteroaryl substituted alkyl radicals having from about 2 to about 50 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 6 to about 25 carbon atoms being preferred. Non-limiting examples include 2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and 3-(pyrimidin-2-yl)-2-methylcyclopentanyl.

As used herein, â€œheterocycloalkylâ€ refers to an optionally substituted, mono-, di-, tri-, or other multicyclic aliphatic ring system that includes at least one, and preferably from 1 to about 4 sulfur, oxygen, or nitrogen heteroatom ring members. Heterocycloalkyl groups can have from about 3 to about 20 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 4 to about 10 carbons being preferred. The heterocycloalkyl group may be unsaturated, and may also be fused to aromatic rings. Non-limiting examples include, for example, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, piperadinyl, decahydroquinolyl, octahydrochromenyl, octahydro-cyclopenta[c]pyranyl, 1,2,3,4,-tetrahydroquinolyl, octahydro-[2]pyrindinyl, decahydro-cycloocta[c]furanyl, and imidazolidinyl.

As used herein, the term â€œspiroalkylâ€ refers to an optionally substituted, alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group. The spiroalkyl group, taken together with its parent group, as herein defined, has 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms. Non-limiting examples of a spiroalkyl group taken together with its parent group include 1-(1-methyl-cyclopropyl)-propan-2-one, 2-(1-phenoxy-cyclopropyl)-ethylamine, and 1-methyl-spiro[4.7]dodecane.

As used herein, the term â€œalkoxyâ€ refers to an optionally substituted alkyl-Oâ€” group wherein alkyl is as previously defined. Non-limiting examples include, for example, include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy.

As used herein, the term â€œaryloxyâ€ refers to an optionally substituted aryl-Oâ€” group wherein aryl is as previously defined. Non-limiting examples include, for example, phenoxy and naphthoxy.

As used herein, the term â€œaralkoxyâ€ refers to an optionally substituted aralkyl-O-group wherein aralkyl is as previously defined. Non-limiting examples include, for example, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, and 3-naphthylheptoxy.

As used herein, the term â€œaryloxyarylâ€ refers to an aryl group with an aryloxy substituent wherein aryloxy and aryl are as previously defined. Aryloxyaryl groups can be optionally substituted. Non-limiting examples include, for example, phenoxyphenyl, and naphthoxyphenyl.

As used herein, the term â€œheteroarylarylâ€ refers to an aryl group with a heteroaryl substituent wherein heteroaryl and aryl are as previously defined. Heteroarylaryl groups can be optionally substituted. Non-limiting examples include, for example, 3-pyridylphenyl, 2-quinolylnaphthalenyl, and 2-pyrrolylphenyl.

As used herein, the term â€œalkoxyarylâ€ refers to an aryl group bearing an alkoxy substituent wherein alkoxy and aryl are as previously defined. Alkoxyaryl groups can be optionally substituted. Non-limiting examples include, for example, para-anisyl, meta-t-butoxyphenyl, and methylendioxyphenyl.

As used herein, â€œcarboxyâ€ refers to a â€”C(â• O)OH group.

As used herein, â€œalkanoylâ€ refers to a â€”C(â• O)-alkyl group, wherein alkyl is as previously defined. Exemplary alkanoyl groups include acetyl (ethanoyl), n-propanoyl, n-butanoyl, 2-methylpropanoyl, n-pentanoyl, 2-methylbutanoyl, 3-methylbutanoyl, 2,2-dimethylpropanoyl, heptanoyl, decanoyl, and palmitoyl.

As used herein, â€œheterocyclicâ€ refers to a monocyclic or multicyclic ring system carbocyclic radical containing from about 4 to about 10 members, and all combinations and subcombinations of ranges therein, wherein one or more of the members is an element other than carbon, for example, nitrogen, oxygen or sulfur. The heterocyclic group may be aromatic or nonaromatic. Non-limiting examples include, for example, pyrrole and piperidine groups.

As used herein, â€œhaloâ€ refers to fluoro, chloro, or bromo.

Typically, substituted chemical moieties include one or more substituents that replace hydrogen. Exemplary substituents include, for example, halo (e.g., F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl, heterocycloalkyl, hydroxyl (â€”OH), nitro (â€”NO₂), cyano (â€”CN), amino (â€”NH₂), â€”N-substituted amino (â€”NHRâ€³), â€”N,N-disubstituted amino (â€”N(Râ€³)Râ€³), carboxyl (â€”COOH), â€”C(â• O)Râ€³, â€”ORâ€³, â€”C(â• O)ORâ€³, â€”NHC(â• O)Râ€³, aminocarbonyl (â€”C(â• O)NH₂), â€”N-substituted aminocarbonyl (â€”C(â• O)NHRâ€³), â€”N,N-disubstituted aminocarbonyl (â€”C(â• O)N(Râ€³)Râ€³), thiol, thiolato (SRâ€³), sulfonic acid (SO₃H), phosphonic acid (PO₃H), S(â• O)₂Râ€³, S(â• O)₂NH₂, S(â• O)₂NHRâ€³, S(â• O)₂NRâ€³Râ€³, NHS(â• O)₂Râ€³, NRâ€³S(â• O)₂Râ€³, CF₃, CF₂CF₃, NHC(â• O)NHRâ€³, NHC(â• O)NRâ€³Râ€³, NRâ€³C(â• O)NHRâ€³, NRâ€³C(â• O)NRâ€³Râ€³, NRâ€³C(â• O)Râ€³ and the like. In relation to the aforementioned substituents, each moiety Râ€³ can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, or heterocycloalkyl, for example.

As used herein, â€œside effectâ€ refers to a consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other then the one sought to be benefited by its administration. In the case, for example, of opioids, the term â€œside effectâ€ may refer to such conditions as, for example, ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea, or vomiting or a combination thereof.

As used herein, â€œileusâ€ refers to the obstruction of the bowel or gut, especially the colon. See, e.g., Dorland's Illustrated Medical Dictionary, p. 816, 27th ed. (W.B. Saunders Company, Philadelphia 1988). Ileus should be distinguished from constipation, which refers to infrequent or difficulty in evacuating the feces. See, e.g., Dorland's Illustrated Medical Dictionary, p. 375, 27th ed. (W.B. Saunders Company, Philadelphia 1988). Ileus may be diagnosed by the disruption of normal coordinated movements of the gut, resulting in failure of the propulsion of intestinal contents. See, e.g., Resnick, J. Am. J. of Gastroenterology, 1992, 751 and Resnick, J. Am. J. of Gastroenterology, 1997, 92, 934. In some instances, particularly following surgery, including surgery of the abdomen, the bowel dysfunction may become quite severe, lasting for more than a week and affecting more than one portion of the gastrointestinal tract. This condition is often referred to as postsurgical (or postoperative) ileus and most frequently occurs after laparotomy (see Livingston, E. H. and Passaro, E. D. Jr., Digestive Diseases and Sciences, 1990, 35, 121). Similarly, postpartum ileus is a common problem for women in the period following childbirth, and is thought to be caused by similar fluctuations in natural opioid levels as a result of birthing stress.

As used herein, â€œeffective amountâ€ refers to an amount of a compound as described herein that may be therapeutically effective to inhibit, prevent, or treat the symptoms of particular disease, disorder, or side effect. Such diseases, disorders and side effects include, but are not limited to, those pathological conditions associated with the administration of opioids (for example, in connection with the treatment and/or prevention of pain), wherein the treatment or prevention comprises, for example, inhibiting the activity thereof by contacting cells, tissues or receptors with compounds of the present invention. Thus, for example, the term â€œeffective amount,â€ when used in connection with opioids, for example, for the treatment of pain, refers to the treatment and/or prevention of the painful condition. The term â€œeffective amount,â€ when used in connection with peripheral Î¼ opioid antagonists, refers to the treatment and/or prevention of side effects typically associated with opioids including, for example, such side effects as ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, nausea, or vomiting or a combination thereof.

As used herein, â€œin combination with,â€ â€œcombination therapyâ€ and â€œcombination productsâ€ refer, in certain embodiments, to the concurrent administration to a patient of antiemetic agents and peripheral Î¼ opioid antagonists, including, for example, the compounds of formula I, or to the concurrent administration to a patient of antiemetic agents, peripheral Î¼ opioid antagonists, and opioids. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

As used herein, â€œdosage unitâ€ refers to physically discrete units suited as unitary dosages for the particular patient to be treated. Each unit may contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention may be dictated by (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s).

As used herein, â€œpharmaceutically acceptableâ€ refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.

As used herein, â€œpharmaceutically acceptable metal saltâ€ refer to derivatives of the disclosed compounds wherein the parent compound is modified by making base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic bases. These physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.

Compounds described herein throughout, can be used or prepared in alternate forms. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide, hydrates, and solvates are also contemplated to be within the scope of the present invention.

Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free-base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxyl groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein throughout that contain, for example, both amino and carboxyl groups, also include reference to their corresponding zwitterions.

As used herein, â€œpatientâ€ refers to animals, including mammals, preferably humans.

As used herein, â€œprodrugâ€ refers to compounds specifically designed to maximize the amount of active species that reaches the desired site of reaction that are of themselves typically inactive or minimally active for the activity desired, but through biotransformation are converted into biologically active metabolites.

As used herein, â€œstereoisomersâ€ refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space.

As used herein, â€œN-oxideâ€ refers to compounds wherein the basic nitrogen atom of either a heteroaromatic ring or tertiary amine is oxidized to give a quaternary nitrogen bearing a positive formal charge and an attached oxygen atom bearing a negative formal charge.

When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The piperidines derivatives useful in the methods, compositions, and kits of the invention as illustrated in formula I can occur as the trans and cis stereochemical isomers at the 3- and 4-positions of the piperidine ring. In the most preferred compounds of formula I, the R²substituent and the R⁴substituent are in the â€œtransâ€ orientation on the piperidine.

In addition to the â€œcisâ€ and transâ€ orientation of the R²substituent and the R⁴substituent of formula I, the absolute stereochemistry of the carbon atoms bearing R²substituent and the R⁴substituent of formula I is also defined as using the commonly employed â€œRâ€ and â€œSâ€ definitions (Orchin et al., The Vocabulary of Organic Chemistry, John Wiley and Sons, Inc., page 126, which is incorporated herein by reference). The preferred compounds of the present invention are those in which the configuration of both the R²substituent and the R⁴substituents of formula I on the piperidine ring are â€œR.â€

Furthermore, asymmetric carbon atoms may be introduced into the molecule depending on the structure of R⁴. As such, these classes of compounds can exist as the individual â€œRâ€ or â€œSâ€ stereoisomers at these chiral centers, or the racemic mixture of the isomers, and all are contemplated as within the scope of the present invention. Preferably, a substantially pure stereoisomer of the compounds of this invention is used, i.e., an isomer in which the configuration at the chiral center is â€œRâ€ or â€œSâ€ , i.e., those compounds in which the configuration at the three chiral centers I preferably 3R, 4R, S or 3R, 4R, R.

As used herein, â€œperipheralâ€ or â€œperipherally-actingâ€ refers to an agent that acts outside of the central nervous system.

As used herein, â€œcentrally-actingâ€ refers to an agent that acts within the central nervous system.

The methods, compositions, and kits of the present invention involve a peripheral opioid antagonist compound. The term â€œperipheralâ€ designates that the compound acts primarily on physiological systems and components external to the central nervous system. In preferred form, the peripheral opioid antagonist compounds employed in the methods of the present invention exhibit high levels of activity with respect to peripheral tissue, such as, gastrointestinal tissue, while exhibiting reduced, and preferably substantially no, CNS activity. The phrase â€œsubstantially no CNS activity,â€ as used herein, means that less than about 20% of the pharmacological activity of the compounds employed in the present methods is exhibited in the CNS, preferably less than about 15%, more preferably less than about 10%, even more preferably less than about 5% and most preferably less than about 1% of the pharmacological activity of the compounds employed in the present methods is exhibited in the CNS.

Furthermore, it is preferred in certain embodiments of the invention where the compound is administered to antagonize the peripheral side effects of an opioid that the compound does not substantially cross the blood-brain barrier and thereby decrease the beneficial activity of the opioid. The phrase â€œdoes not substantially cross,â€ as used herein, means that less than about 20% by weight of the compound employed in the present methods crosses the blood-brain barrier, preferably less than about 15% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight and most preferably 0% by weight of the compound crosses the blood-brain barrier. Selected compounds can be evaluated for CNS penetration by determining plasma and brain levels following intravenous administration.

U.S. Pat. No. 6,451,806 and U.S. Pat. No. 6,469,030 disclose methods and compositions comprising opioids and opioid antagonists, including peripheral Î¼ opioid antagonists, the disclosures of which are incorporated herein by reference in their entirety. The methods and compositions are useful, inter alia, for treating and/or preventing pain and for treating and/or preventing side effects associated with opioids including ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, vomiting or nausea or a combination thereof, particularly postoperative or postpartum ileus, opioid bowel dysfunction, postoperative nausea, or postoperative vomiting. The methods, compositions, and kits of the present invention are related to peripheral Î¼ opioid antagonists and are directed to combinations of peripheral Î¼ opioid antagonists with centrally-acting antiemetic agents and with centrally-acting antiemetic agents and opioids, for the treatment and prevention, for example, of pain and/or side effects associated with opioids, including ileus, pruritis, constipation, urinary retention, biliary spasm, opioid bowel dysfunction, colic, vomiting or nausea or a combination thereof, particularly postoperative or postpartum ileus, opioid bowel dysfunction, postoperative nausea, or postoperative vomiting.

Accordingly, in one embodiment, the present invention provides methods comprising the steps of:

a. providing a composition, comprising:

- (i) a pharmaceutically-acceptable metal salt of at least one compound of formula I:

[Image Omitted]

- - wherein:
  - R¹is hydrogen or alkyl;
  - R²is hydrogen, alkyl or alkenyl;
  - R³is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl or aralkyl;
  - R⁴is hydrogen, alkyl or alkenyl;
  - A is OR⁵or NR⁶R⁷;
  - R⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R⁶is hydrogen or alkyl;
  - R⁷is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, cycloalkyl-substituted alkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aralkyl, aralkyl, or alkylene substituted B or, together with the nitrogen atom to which they are attached, R⁶and R⁷form a heterocyclic ring;
  - B is

[Image Omitted]

- C(â• O)W or NR⁸R⁹;
  - R⁸is hydrogen or alkyl;
  - R⁹is hydrogen, alkyl, alkenyl, cycloalkyl-substituted alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, aryl or aralkyl or, together with the nitrogen atom to which they are attached, R⁸and R⁹form a heterocyclic ring;
  - W is OR¹⁰, NR¹¹R¹², or OE;
  - R¹⁰is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R¹¹is hydrogen or alkyl;
  - R¹²is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, aralkyl or alkylene substituted C(â• O)Y or, together with the nitrogen atom to which they are attached, R¹¹and R¹²form a heterocyclic ring;
  - E is

[Image Omitted]

- alkylene substituted (Câ• O)D, or â€”R¹³OC(â• O)R¹⁴;
  - R¹³is alkyl substituted alkylene;
  - R¹⁴is alkyl;
  - D is OR¹⁵or NR¹⁶R¹⁷;
  - R¹⁵is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R¹⁶is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl or cycloalkenyl-substituted alkyl;
  - R¹⁷is hydrogen or alkyl or, together with the nitrogen atom to which they are attached, R¹⁶and R¹⁷form a heterocyclic ring;
  - Y is OR¹⁸or NR¹⁹R²⁰;
  - R¹⁸is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl;
  - R¹⁹is hydrogen or alkyl;
  - R²⁰is hydrogen, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted alkyl, or aralkyl or, together with the nitrogen atom to which they are attached, R¹⁹and R²⁰form a heterocyclic ring;
  - R²¹is hydrogen or alkyl; and
  - n is 0 to 4;
- (ii) at least one bulking agent that crystallizes;
- (iii) at least one weak base; and
- (iv) water;
  - wherein said composition has an initial pH of at least about 10.5; and
    b. adjusting the pH of said composition to a final pH in the range of about 9 to about 11;

wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration.

The methods of the present invention are useful, inter alia, for forming composition having improved solubility and bioavailability, particularly via injectable formulations, such as those administered intravenously, relative to prior art compositions, including compositions containing the same or different components that have not been processed in the same way to form the final formulation (such as pH adjustments, forming the pharmaceutically-acceptable metal salt of the active ingredient in situ, lyophilization, and/or annealing) or that do not have same physical properties (such as density or porosity).

In preferred embodiments of the method, upon reconstitution the solution is formed in less than about five minutes under ambient conditions, more preferably, less than about one minute under ambient conditions, and, even more preferably, less than about 30 seconds under ambient conditions, preferably by simple shaking, stirring, or mixing. As used herein, â€œunder ambient conditionsâ€ means under normal atmospheric pressure and room temperature in the range of about 10Â° C. to about 50Â° C. without the addition of direct heating or cooling. The formation of the solution may determined, for example, by the presence of a clear solution upon mixing by visual observation, preferably using a microscope light projected through a diaphragm into the solution, by Coulter counter, or by light-scattering instruments.

In preferred embodiments of the method, the initial pH is adjusted to at least about 11. Preferably, the initial pH does not exceed about pH 12, as this high pH may lead to instability of the composition. The initial pH may be adjusted with any suitable pharmaceutically acceptable pH adjusting agent, including a strong or weak acid or base, preferably pharmaceutically-acceptable metal carbonate, pharmaceutically-acceptable metal bicarbonate, pharmaceutically-acceptable metal hydroxide, or hydrochloric acid, more preferably where the pharmaceutically-acceptable metal is sodium, and even more preferably, sodium carbonate or sodium bicarbonate, and yet more preferably sodium carbonate. Sodium carbonate and sodium bicarbonate are preferred because they generate carbon dioxide and thereby contribute to the desirable lower density of the composition.

In preferred embodiments of the method, the final pH is adjusted to a range of about 9.5 to about 10.5. The final pH may be adjusted with any suitable pharmaceutically acceptable pH adjusting agent, including a strong or weak acid or base, preferably sodium hydroxide or hydrochloric acid.

In certain preferred embodiments of the method, the pharmaceutically-acceptable metal salt of at least one compound of formula I is prepared in situ.

In certain preferred embodiments of the method, the pharmaceutically-acceptable metal salt of the compound of formula I is formed from at least one weak base, wherein said weak base is added in at least about an equimolar amount to the compound of formula I. Preferably, there is not a great excess of weak base, as such excess may lead to an undesirably high pH (greater than about 12) which may contribute to instability of the composition.

In certain preferred embodiments of the method, the composition is prepared by first admixing said bulking agent and a pharmaceutically-acceptable metal salt of said weak base in water and then adding said compound of formula I to said admixture.

In certain other preferred embodiments of the method, the composition is prepared by substantially simultaneously admixing said compound of formula I, said bulking agent and a pharmaceutically-acceptable metal salt of said weak base in water. As used in the context of admixing, â€œsubstantially simultaneouslyâ€ refers to adding the components together within about five minutes, preferably within about one minute, and more preferably within about 30 seconds of each other.

In preferred embodiments of the invention, the pharmaceutically acceptable metal is an alkali metal, such as sodium, potassium, or lithium, or an alkaline earth metal, such as calcium, or magnesium, or combinations thereof. Sodium, calcium, and magnesium are preferred. Sodium is more preferred. It is preferred to avoid potassium for parenteral administration.

The method may further comprise the step of drying said composition to remove at least a portion of said water to form a partially or fully dried product. In preferred embodiments, the composition is annealed during the drying step. As used herein, â€œannealedâ€ means the process of heating and then slowly cooling a material, including repeated cycles of heating and cooling. Suitable drying means include lyophilization (freeze-drying), spray drying, vacuum drying, and combinations thereof. The preferred drying means is via lyophilization.

The method may yet further comprise the step of reconstituting said dried product by combining therewith a pharmaceutically acceptable solvent to form a solution of said dried product.

In preferred embodiments of the method, the weak base is bicarbonate or carbonate, more preferably carbonate. These weak bases are preferred because they generate carbon dioxide and thereby contribute to the desirable lower density of the composition.

In preferred embodiments of the method, the pharmaceutically acceptable solvent is aqueous, preferably, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, or lactated Ringer's solution.

In preferred embodiments, the method of the invention further comprises the step of administering said solution of said dried product to a patient. The composition may be administered prior to surgery, during surgery, and/or in the absence of surgery.

In preferred embodiments, the composition is administered via injection, particularly subcutaneous injection, intramuscular injection, or intravenous injection.

Any pharmaceutically acceptable bulking agent that crystallizes may be used in the composition of the invention. As used herein, â€œbulking agentâ€ refers to an inert diluent or filler that acts as a carrying agent for the drug substance (in the case of the present invention, the compound of formula I). Suitable bulking agents may be found in the Handbook of Pharmaceutical Excipients, 3^rdEd. Washington, D.C: American Pharmaceutical Association, 1998, the disclosure of which is incorporated herein by reference. In certain other preferred embodiments, the bulking agent is a polyol, such as a carbohydrate or sugar alcohol. Suitable carbohydrates include sucrose, trehalose, lactose, maltose, and mixtures thereof. Suitable sugar alcohols include mannitol, xylitol, erythritol, lactitol, isomalt, polyalditol, maltitol, and mixtures thereof. Mannitol is particularly preferred.

While not wishing to be bound by theory, it is believed that bulking agents that crystallize produce a desirable cake structure with good mechanical properties. These properties are important to ensure rapid reconstitution rates. Additionally, rapid nucleation of a bulking agent that crystallizes during lyophilization produces a cake with a much greater surface area, thus resulting in higher diffusive flux and faster sublimation rates. Bulking agents that are in an amorphous form require a high amount of energy to dry and do not produce a desirable cake structure. Since initial ice crystal size depends upon contributions from nucleation and growth rate, small ice crystals formed in systems containing amorphous solids produce pores with lower surface area per volume. This lower surface area results in lower diffusive flux and lower sublimation rates.

In certain embodiments, the invention is directed to compositions, comprising:

a. a pharmaceutically-acceptable metal salt of at least one compound of formula I;
b. at least one bulking agent that crystallizes;

wherein said composition has a density of less than about 1.0 g/cm³;

wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration.

Preferably, the composition has a density of less than about 0.5 g/cm³, more preferably, less than about 0.2 g/cm³, even more preferably less than about 0.15 g/cm³, yet even more preferably in the range of about 0.05 g/cm³to about 0.12 g/cm³, more preferably, a density in the range of about 0.06 g/cm³to about 0.08 g/cm³.

In certain other embodiments, the invention is directed to compositions, comprising:

a. a pharmaceutically-acceptable metal salt of at least one compound of formula I;
b. at least one bulking agent that crystallizes;
c. less than about 0.5% by weight, based on the total weight of the composition, of a solubilizing surfactant;
d. less than about 10% by weight, based on the total weight of the composition, of a non-aqueous solvent; and
e. less than about 0.5% by weight, based on the total weight of the composition, of cyclodextrin;

wherein, upon administration to a patient, said composition has improved solubility and bioavailability for oral or parenteral administration.

These compositions provide improved solubility and bioavailability for oral or parenteral administration because they permit the compound of formula I to more readily go into solution when reconstituted from dried product than would otherwise be the case for the compounds of formula I, which have a very low water solubility due to their zwitterionic nature.

Preferably, the pharmaceutically-acceptable metal salt of a compound of formula I is present at a level of at least about 0.1 mg/mL, more preferably, at a level of at least about 1 mg/mL, and even more preferably, at a level of at least about 2 mg/mL.

Preferably, compositions of the invention further comprising at least one pharmaceutically acceptable solvent. In preferred embodiments of the composition, the pharmaceutically acceptable solvent is aqueous, preferably, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, or lactated Ringer's solution.

Preferably, the composition has a shelf life of at least about 18 months. As used herein, â€œshelf lifeâ€ refers to the time from the date of manufacture and packing of the formulation, until its chemical or biological activity is not less than a predetermined level of labeled potency, generally about 90%, and its physical characteristics have not changed appreciably or deleteriously.

In certain preferred embodiments, the compositions of the invention may include an opioid, a prodrug of an opioid, and/or pharmacologically-active metabolites, provided that its inclusion does not interfere with the solubility or bioavailability of the compound of formula I. Suitable opioids include alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol, and mixtures thereof. Preferred opioids include morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, and tramadol.

Compositions of the present invention may further include one or more other active ingredients conventionally employed in analgesic and/or cough-cold-antitussive combination products, provided that its inclusion does not interfere with the solubility or bioavailability of the compound of formula I. Such conventional ingredients include, for example, aspirin, COX-2 inhibitors, acetaminophen, phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/or guaifenesin. Typical or conventional ingredients that may be included are described, for example, in the Physicians' Desk Reference, 2004, the disclosure of which is hereby incorporated herein by reference, in its entirety.

In addition, the composition of the invention may further include one or more compounds that may be designed to enhance the analgesic potency of the opioid and/or to reduce analgesic tolerance development, provided that its inclusion does not interfere with the solubility or bioavailability of the compound of formula I. Such compounds include, for example, dextromethorphan or other NMDA antagonists (Mao, M. J. et al., Pain 1996, 67, 361), L-364,718 and other CCK antagonists (Dourish, C. T. et al., Eur. J. Pharmacol., 1988, 147, 469), NOS inhibitors (Bhargava, H. N. et al., Neuropeptides, 1996, 30, 219), PKC inhibitors (Bilsky, E. J. et al., J. Pharmacol. Exp. Ther. 1996, 277, 484), and dynorphin antagonists or antisera (Nichols, M. L. et al., Pain, 1997, 69, 317). The disclosures of each of the foregoing documents are hereby incorporated herein by reference, in their entireties.

Other opioids, optional conventional opioid components, and optional compounds for enhancing the analgesic potency of the opioid and/or for reducing analgesic tolerance development, that may be employed in the methods and compositions of the present invention, in addition to those exemplified above, would be readily apparent to one of ordinary skill in the art, once armed with the teachings of the present disclosure.

Preferred 4-aryl-piperidine derivatives include, for example, the compounds disclosed in U.S. Pat. No. 5,250,542; U.S. Pat. No. 5,159,081; U.S. Pat. No. 5,270,328; and U.S. Pat. No. 5,434,171, U.S. Pat. No. 6,451,806 and U.S. Pat. No. 6,469,030, the disclosures of which are hereby incorporated herein by reference, in their entireties.

In preferred embodiments, the compound of formula I is a trans 3,4-isomer.