Phenylalkylcarboxylic acid delivery agents   

FIELD OF THE INVENTION

The present invention relates phenylalkylcarboxylic acid compounds and compositions which facilitate the delivery of active agents.

BACKGROUND OF THE INVENTION

Conventional means for delivering active agents are often severely limited by biological, chemical and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, and/or the target itself. Biologically and chemically active agents are particularly vulnerable to such barriers.

In the delivery to animals of biologically active and chemically active pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical barriers are the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.

These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents may be rapidly rendered ineffective or destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs may prohibit absorption.

Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.

Proteinoid microspheres have been used to deliver pharmaceuticals. See, for example, U.S. Pat. Nos. 5,401,516; 5,443,841; and Re. 35,862. In addition, certain modified amino acids have been used to deliver pharmaceuticals. See, for example, U.S. Pat. Nos. 5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5,866,536.

More recently, a polymer has been conjugated to a modified amino acid or a derivative thereof via a linkage group to provide for polymeric delivery agents. The modified polymer may be any polymer, but preferred polymers include, but are not limited to, polyethylene glycol (PEG), and derivatives thereof. See, for example, International Patent Publication No. WO 00/40203.

However, there is still a need for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents by various routes.

SUMMARY

The present invention provides phenylalkylcarboxylic acid compounds and compositions which facilitate the delivery of active agents (e.g. biologically active agents). Delivery agent compounds of the present invention include those having the formula:

and pharmaceutically acceptable salts thereof, wherein n is 1-12, and R1-R5 are independently hydrogen, C1-C6 alkyl, C2-C4 alkenyl, halogen, C1-C4 alkyloxy, hydroxyl, C6-C14 aryloxy, or C1-C6 alkylhalo (e.g. C1 alkylhalo) group.

According to one embodiment, n ranges from 1 to 9. For example, n may be 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3 or 1-2.

According to another embodiment, at least one of R1 to R5 is methyl, methoxy, hydroxy or halogen group (e.g., Cl or F).

Mixtures of these delivery agent compounds may also be used.

The invention also provides a pharmaceutical composition comprising at least one delivery agent compound of the present invention, and at least one active agent (e.g. a biologically active agent). When administered with an active agent, delivery agents of the present application improve the bioavailability of the active agent compared to administration of the active agent without the delivery agent compound.

Also provided is a dosage unit form comprising a pharmaceutical composition of the present invention. The dosage unit form may be in the form of a liquid or a solid, such as a tablet, capsule or particle, including a powder or sachet.

Another embodiment is a method for administering an active agent to an animal, particularly an animal in need of the active agent, by administering a pharmaceutical composition comprising at least one of delivery agent compound of the present invention and the active agent to the animal. Preferred routes of administration include the oral and intracolonic routes, particularly the oral route.

Yet another embodiment of the present invention is a method of treating a disease or for achieving a desired physiological effect in an animal (e.g. a human) by administering to the animal the pharmaceutical composition of the present invention.

Yet another embodiment of the present invention is a method of preparing a pharmaceutical composition of the present invention by mixing at least one delivery agent compound of the present invention, and at least one active agent.

Yet another embodiment of the present invention is a method of increasing the bioavailability (e.g., the oral bioavailability) of a pharmaceutical composition containing an active agent (e.g., a biologically active agent) comprising adding a delivery agent compound of the present invention to the pharmaceutical composition.

DETAILED DESCRIPTION

The term “alkyl” refers to a straight-chained, branched, or substituted monovalent aliphatic hydrocarbon group containing no double or triple carbon-carbon bonds. Examples of alkyl group include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, and 1-dimethylethyl(t-butyl).

The term “alkenyl” refers to a straight-chained, branched, or substituted monovalent aliphatic hydrocarbon group containing at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

The term “alkylene” refers to a straight-chained, branched or substituted divalent aliphatic hydrocarbon group containing no double or triple bonds.

The term “alkyloxy” refers to an alkyl group attached via an oxygen linkage to the rest of the molecule. Examples of alkyloxy groups include, but are not limited to, —OCH3, and —OC2H5 groups.

The term “aryl” refers to an monovalent C6-C14 aromatic group, i.e. a monovalent group having one or more unsaturated carbon rings. Examples of aryl groups, include, but are not limited to, phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term “alkyl(arylene)” refers to a divalent group containing an aromatic group with an alkyl group before and/or after the aromatic group.

The term “aryloxy” refers to an C6-C14 aryl group attached via an oxygen linkage to the rest of the molecule, such as —OC6H5.

The term “insulin” includes recombinant forms of insulin (e.g. recombinant human insulin), analogs of insulin lispro or Humalog®) as well as regular forms of insulin of human or other animal origin.

The term “heparin” includes unfractionated heparin, low molecular weight heparin, very low molecular weight heparin, of recombinant, human, or other animal origin.

The term “LHRH” or “luteinizing hormone-releasing hormone” refers to a hormone produced by the hypothalamus that signals the anterior pituitary gland to begin secreting luteinizing hormone and follicle-stimulating hormone.

The term “rhGH” refers to recombinant human growth hormone.

The term “caspofungin” or “caspofungin acetate” refers to a water-soluble, semisynthetic lipopeptide derived from the fungus, Glarea lozoyensis, that has activity against Aspergilllus and Candida species. Caspofugin acetate (Cancidas®) has been approved by the FDA and is indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other antifungal agents.

Unless otherwise specified, the term “substituted” as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, C1-C6 alkyl, including methyl, ethyl, propyl, isopropyl, normal or iso-butyl; C2-C4 alkenyl, C1-C4 alkyloxy, aryl, halo, alkylhalo, or aryloxy groups.

The term “about” means generally means within 10%, preferably within 5%, and more preferably within 1% of a given range.

The term “short stature” refers to a subject with a size (e.g. a height) that is significantly below what is considered normal. Growth hormone, e.g., human growth hormone, is indicated for short stature.

Delivery agent compounds of the present invention include those compounds represented by Formula I below, and pharmaceutically acceptable salts thereof:

wherein

n is 1-12; and

R1-R5 are independently hydrogen, C1-C6 alkyl, C2-C4 alkenyl, halo, C1-C4 alkyloxy, hydroxyl, C6-C14 aryloxy, or C1-C6 alkylhalo group (e.g. C1 alkylhalo).

In various embodiments, n may be 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3 or 1-2.

In another embodiment of the present invention, delivery agent compounds of the present invention include those compounds represented by Formula I above in which at least one of R1-R5 is a methyl, methoxy, alkyloxy, hydroxy or halogen group. In a preferred embodiment, delivery agent compounds include those in which n is defined as in the preceding paragraph and at least one of R1-R5 is a methyl, methoxy, alkyloxy, hydroxy, or halogen group.

In one embodiment of the present invention, delivery agent compounds are selected from Formula I above, in which at least one of R1-R5 is a methyl group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of R1-R5 is a methoxy group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of R1-R5 is a hydroxy group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of R1-R5 is an aryloxy group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of R1-R5 is an alkyloxy group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of R1-R5 is a C1 alkylhalo group. In another embodiment, delivery agent compounds are selected from Formula I above in which at least one of R1-R5 is a halogen, preferably at least one of R1-R5 is a chlorine atom or at least one of R1-R5 is a fluorine atom.

In one embodiment of the present invention, the compounds listed in Table 1 are excluded as delivery agents of Formula I. However, in various embodiments these compounds may be included in compositions that further include an active agent (e.g., a biologically active agent).

The delivery agent compounds may be in the form of the free base or pharmaceutically acceptable salts thereof, such as pharmaceutically acceptable acid addition salts. Suitable salts include, but are not limited to, organic and inorganic salts, for example ammonium, acetate salt, citrate salt, halide (preferably hydrochloride), hydroxide, sulfate, nitrate, phosphate, alkyloxy, perchlorate, tetrafluoroborate, carboxylate, mesylate, fumerate, malonate, succinate, tartrate, acetate, gluconate, and maleate. Preferred salts include, but are not limited to, citrate and mesylate salts. The salts may also be solvates, including ethanol solvates, and hydrates.

Salts of the delivery agent compounds of the present invention may be prepared by methods known in the art. For example, citrate salts and mesylate salts may be prepared in ethanol, toluene and citric acid.

The delivery agent compound may be purified by recrystallization or by fractionation on one or more solid chromatographic supports, alone or linked in tandem. Suitable recrystallization solvent systems include, but are not limited to, ethanol, water, heptane, ethyl acetate, acetonitrile, acetone, methanol, and tetrahydrofuran (THF) and mixtures thereof. Fractionation may be performed on a suitable chromatographic support such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase chromatography using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water or an appropriate buffer as the mobile phase. When anion exchange chromatography is performed, preferably a 0-500 mM sodium chloride gradient is employed.

The delivery agent may contain a polymer conjugated to it by a linkage group selected from the group consisting of —NHC(O)NH—, —C(O)NH—, —NHC(O)—; —OOC—, —COO—, —NHC(O)O—, —OC(O)NH—, —CH2NH—NHCH2—, —CH2NHC(O)O—, —OC(O)NHCH2—, —CH2NHCOCH2O—, —OCH2C(O)NHCH2—, —NHC(O)CH2O—, —OCH2C(O)NH—, —NH—, —O—, and carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid. The polymer may be any polymer including, but not limited to, alternating copolymers, block copolymers and random copolymers, which are safe for use in mammals. Preferred polymers include, but are not limited to, polyethylene; polyacrylates; polymethacrylates; poly(oxyethylene); poly(propylene); polypropylene glycol; polyethylene glycol (PEG); and derivatives thereof and combinations thereof. The molecular weight of the polymer typically ranges from about 100 to about 200,000 daltons. The molecular weight of the polymer preferably ranges from about 200 to about 10,000 daltons. In one embodiment of the present invention, the molecular weight of the polymer ranges from about 200 to about 600 daltons and more preferably ranges from about 300 to about 550 daltons.

Non-limiting examples of delivery agent compounds of Formula I include those shown below and pharmaceutically acceptable salts thereof:

Compounds 22-74 (Table 1) were purchased from commercially available sources for utilization as delivery agents.

TABLE 1 Commercial compounds utilized as delivery agents Delivery Agent Compound # Purchased from Chemical name 22 Sigma-Aldrich Benzeneacetic acid (St. Louis, MO) 23 Johnson Matthey 8-Phenyloctanoic acid (London, UK) 24 Lancaster 10-Phenyldecoic acid (Windham, NH) 25 Lancaster 4-(4-Methylphenyl)butanoic acid 26 Lancaster 3-(3-Hydroxyphenyl)propanoic acid 27 Sigma-Aldrich 3-(p-Hydroxyphenyl)propanoic acid 28 Sigma-Aldrich 5-Phenylpentanoic acid 29 Sigma-Aldrich 6-Phenylhexanoic acid 30 Matrix Scientific 2-Phenoxyphenylethanoic acid (Columbia, SC) 31 Matrix Scientific 4-Phenoxyphenylethanoic acid 32 Lancaster 7-Phenylheptanoic acid 33 Johnson Matthey 3-(4-Methylphenyl)propanoic acid 34 Johnson Matthey 3-(3,4-Dihydroxyphenyl)propanoic acid 35 Johnson Matthey 3-(2-Hydroxyphenyl)propanoic acid 36 Sigma-Aldrich 3-[4-(Trifluoromethyl)phenyl]propanoic acid 37 Sigma-Aldrich 3-[2,5-Bis(Trifluoromethyl)phenyl]propanoic acid 38 Trans World 3-(2-Fluorophenyl)propanoic acid Chemicals (Rockville, MD) 39 Trans World 3-(3-Fluorophenyl)propanoic acid Chemicals 40

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