Patent Application
20060264353
The present invention relates to novel compositions of matter, and more particularly, to the novel combination of prostaglandin compounds of the F-series (PGF) with antimicrobial peptides, and the use of such compositions for the treatment of increased intraocular pressure, such as that caused by glaucoma and the reduction of ocular hypertension.
The prostaglandins are a family of 20 carbon atom fatty acids, being structural derivatives of prostanoic acid, which exhibit useful activity in a wide variety of biological systems. Accordingly, prostaglandins represent useful pharmacological agents in the treatment and prevention of a wide variety of disease conditions. For a fuller discussion of prostaglandins and their uses, see Oates, et al., New England J. Med. Vol. 319, No. 11, pages 689-698 and Vol. 319, No. 12, pages 761-768 (1988) and references cited therein.
The prostaglandins are a family of 20 carbon atom fatty acids, being structural derivatives of prostanoic acid, which exhibit useful activity in a wide variety of biological systems. Accordingly, prostaglandins represent useful pharmacological agents in the treatment and prevention of a wide variety of disease conditions. For a fuller discussion of prostaglandins and their uses, see Oates, et al., New England J. Med., Vol. 319, No. 11, pp. 689-698 and Vol. 319, No. 12, pp. 761-768 (1988) and the references cited therein.
Prostaglandin F2α (PGF2α) is a naturally-occurring prostaglandin which is widely manufactured and sold under a variety of trade names as an abortifacient, among other uses. See monograph 8065, page 1354 of The Merck Index, 12th edition (1996). It is also well known in the art that naturally-occurring prostaglandins can be topically applied to lower intraocular pressure. However, naturally-occurring prostaglandins generally cause inflammation and surface irritation of the eye.
Analogs of PGF2α which incorporate aromatic groups and other substituents into the omega chain have been prepared and found to be more potent and selective pharmacologic agents than the naturally-occurring compounds. An exemplary PGF2α analog of this type is fluprostenol, 16-(meta-trifluoromethylphenoxy)-17,18,19,20 tetranor PGF2α, and its pharmacologic profile is described in monograph 4231, page 711 of The Merck Index, 12th edition (1996). Unfortunately, the known synthetic analogs also produce the same undesirable side effects as the naturally-occurring compounds. There is, therefore, a need in the art for less inflammatory compounds for reducing intraocular pressure.
A number of simple PGF2α analog esters have been found to be potent and selective agents useful for the treatment of ocular hypertension. For example, latanoprost is the isopropyl ester of 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2α and is widely marketed for the clinical treatment of glaucoma under the trade name Xalatan. See monograph 5387, page 918 of The Merck Index, 12th edition (1996). Likewise, the isopropyl ester of fluprostenol and of similar PGF2α analogs, such as cloprostenol, are specifically claimed as ocular antihypertensive agents in U.S. Pat. No. 5,665,773. The structures of naturally-occurring PGF2α (Structure I), fluprostenol (Structure II), and latanoprost (Structure III), and bimatoprost (Structure IV) are shown hereinbelow. For a review of these agents, see Lindén and Alm, Drugs and Aging, Vol. 14, No. 5, pp. 387-398 (1999).
The amides and esters of PGF2α and its analogs are believed to act as prodrugs in the eye, in that the ester form which is administered is hydrolyzed by endogenous ocular esterase enzymes, releasing the PGF2α analog free acid as the active pharmacologic agent. However, this also releases a toxic and irritant small aliphatic alcohol such as isopropanol or methanol into the eye. In the case of bimatoprost, ethylamine is released into the eye. While highly effective in reducing intraocular pressure, all of the drugs currently in use cause a significant level of eye irritation.
In addition to the foregoing, the isopropyl esters of PGF2α analog compounds such as latanoprost and fluprostenol are highly viscous, glassy oils which are difficult to handle and to formulate into ophthalmic solutions. Worse yet, these compounds are prone to the retention of potentially toxic process solvents. There is, therefore, a need for a form of the prostaglandin analogs which is easier to handle and which does not release an irritant alcohol upon hydrolysis.
In addition to the irritation caused by the prostaglandins themselves, and particularly the naturally-occurring and synthetic prostaglandins of the type presently on the market, the preservatives typically used in ophthalmic solutions are known to irritate a large percentage of the population. Thus, despite the fact that the prostaglandins represent an important class of potent therapeutic agents for the treatment of glaucoma, the unwanted side effects of these drugs, particularly ocular irritation and inflammation, are the chief reasons for patient withdrawal from the use of these drugs. There is, therefore, a need for a less irritating ophthalmic formulation for the therapeutic prostaglandin compounds.
This problem has been addressed in the art by creating novel prostaglandins that, in their free acid active form, are more selective and less prone to bind to, and activate, the receptors responsible for side effects. As an example, internal esters of PGF2α analogs have been devised by creating a carbon-oxygen bond between the alcohol group at C-15 and C-1 carboxylic acid. This creates a macrocyclic lactone that has novel and desirable characteristics. In fact, some of the novel analogs form highly crystalline structures that are advantageously easy to formulate into ophthalmic solutions. The hydrolysis of these PGF2α analog 1,15-lactones releases only the active PGF2α analog free acid, without the production of a small aliphatic alcohol coproduct. Thus, these compounds are ideal and unique prodrugs for the treatment of glaucoma and other disorders causing an increase in intraocular pressure in the eyes of humans or animals.
Examples of these newly developed macrocyclic internal 1,15-lactones of fluprostenol and related PGF analogs are shown hereinbelow as Structures V-VII. For a more complete description, however, see International Patent Publication No. 01/57015 published under the Patent Cooperation Treaty on Aug. 9, 2001, the disclosure of which is incorporated herein by reference.
Although the macrocyclic internal 1,15-lactones of fluprostenol and related PGF analogs themselves are less irritating, the synthetic preservatives commonly used in ophthalmic solutions, such as benzalkonium chloride and thimerosal, are irritating to many patients, especially those with allergy or chemical hypersensitity. There is, therefore, a need for ophthalmic solutions that do not contain synthetic chemical preservatives.
Antimicrobial peptides, such as lactoferrin and lactoferricin, are produced naturally in the human eye. However, these antimicrobial peptides have not been used heretofore as a preservatives in ophthalmic solutions.
Antimicrobial peptides have been known to science since the early 1980s, when they were discovered in insects (see, Steiner, et al., Nature, Vol. 292, pages 246-268 (1981); in amphibians (see, Simmaco, et aL, Biopolymers, Vol. 47, pages 345-450 (1998) and Zasloff, M. Proc. Natl. Acad. Sci., USA 84, pages 5449-5453 (1987); and in humans (see, Selstad, et al., J. Biol. Chem., Vol. 267, pages 4292-4295 (1992)). Perhaps the best known antimicrobial peptide is lactoferrin, found naturally in human tears and in human milk, and the defensive antimicrobial peptide lactoferricin, which is derived from it. A listing of the names and structures of all of the currently known antimicrobial peptides, can be found on the internet at the following the web site: http://www.bbcm.univ.trieste.it/˜tossi/antimic.html.
Antimicrobial peptides have applications as antibiotics, for example, Pexiganan, a derivative of the defensive antimicrobial peptide from the skin of the African clawed frog, is under development as a topical antibiotic for treating diabetic skin ulcers. However, the combination of antimicrobial peptides with prostaglandin ester, amide, and especially internal lactone prodrugs, in ophthalmic formulations, is novel and results in a synergistic and beneficial reduction in the incidence of irritant side effects. These irritant side effects include, melanocyte hyperplasia, which is of concern in that it could lead to the more dangerous cellular dysplasia, with chronic application of the drug. This irritant side effect has also been recognized more recently in the form of iridial melanocyte hyperplasia and hyperpigmentation which has been documented in patients treated with ophthalmic solutions of isopropyl esters, such as Unoprostone (See page 2 of NDA 21-214 for Rescula™ Ciba Vision). Thus, the benefits of this invention extend beyond improved patient comfort, compliance, and acceptance, but also to patient safety.
It is, therefore, an object of this invention to provide improved ophthalmic formulations, and particularly ophthalmic formulations for prostaglandin compounds that are useful for the reduction of intraocular pressure with less inflammation and toxic side effects.
The foregoing and other objects are achieved by this invention which provides, in a composition of matter aspect, a combination of prostaglandin compounds and antimicrobial peptides, and more particularly a combination of prostaglandin compounds of the F-series (PGF) with antimicrobial peptides. In order to improve on the therapeutic index of prostaglandin-containing ophthalmic formulations, and in particular, to decrease the incidence of unwanted side effects, such as hyperemia, irritation, and inflammation of the conjunctiva, the active prostaglandin ingredients have been formulated into ophthalmic solutions which contain no synthetic chemical preservatives, such as benzalkonium chloride, BHT, or similar irritating phenylaromatic preservatives, but which instead contain antimicrobial peptides, and in particularly preferred embodiments, antimicrobial peptides of human derivation, such as lactoferrin. The formulation is, therefore, ideally suited to be dispensed in multidose format.
The formulation which is, in preferred embodiments, a combination of a prostaglandin prodrug with an antimicrobial peptide preservative, further reduces the incidence of irritant side effects, results in better patient compliance, and reduced ocular inflammation. The term prodrug is meant to include a prostaglandin ester, prostaglandin amide, or most preferably, a prostaglandin lactone, In particularly preferred embodiments, the prostaglandin compound is a macrocyclic internal 1,15-lactone, and in particular internal 1,15-lactones of PGF2α analogs, such as the 16-aryloxy prostaglandin analogs, illustratively fluprostenol or cloprostenol.
For the purposes of this patent, however, the term “prostaglandin” is intended to mean any one of the prostanoic acid derivatives which include the ring type A, B, C, D, E, F, G, H, I, J and K, but most particularly those of the F-type. The term “derivative” is intended to mean all compounds which have a chemical affinity, resemblance, or structural character which clearly associates them with the prostanoids and in particular, prostanoic acid or PGF2α. The term “analog” is intended to mean any somewhat modified version of a natural product, in this case a prostaglandin, or a related synthetic analog, wherein a number of atoms such as carbon, hydrogen, oxygen or heteroatoms such as nitrogen, sulfur or halide have been added or deleted from the parent structure, so as to yield a new molecular compound.
The preferred prostaglandin compounds for use in the formulation composition of the present invention have the general Formula I:
wherein X is O, S, NH or CH2;
R1 and R2 are the same and are either H, CH3 or F;,
R9 is H, or C1-C20 straight chain, saturated or unsaturated or branched acyl;
R11 is H, or C1-C20 straight chain, saturated or unsaturated or branched acyl;
represents any combination of a single bond, or a cis or trans double bond;
Z is H, Cl, Br, I, CF3, CH3, or C1-C10 straight chain or branched alkyl;
Y is O, S, NH or CH2.
In preferred embodiments of the present invention, the prostaglandin component of the formulation is an internal 1,15-lactone that is an analog of the PGF2α analog fluprostenol. In particular, analogs of fluprostenol, having the structure of Formula I wherein R9 and R11 are H; Y is one of the polar substituents O, S, or NH; and Z is CH3 are highly crystalline and therefore, are readily formulated into ophthalmic solutions for topical application.
In specific preferred embodiments of the present invention, the prostaglandin component is the 1-15-lactone of fluprostenol (Structure V), the 1,15-lactone of cloprostenol (Structure VI) and the 1,15-lactone of latanoprost (Structure VII).
It is also contemplated that prostaglandin compounds for use in the formulation composition of the present invention have the general Formula II, and particularly include, the known prostaglandin analogs of Formula II:
wherein D is
wherein R8 is hydrogen or hydroxy;
wherein R3 and R4 are hydrogen, methyl or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro, only when the other is hydrogen or fluoro;
wherein M1 is
wherein R5 is hydrogen or methyl;
wherein R7 is —(CH2)m—CH3, wherein m is one to 5, inclusive, cis-CH═CH—CH2—CH3, or
wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, the various T's being the same or different, s is zero, one, 2, or 3, and Z3 is oxa or methylene, with the proviso, that not more than two T's are other than alkyl, and the further proviso that Z3 is oxa only when R3 and R4 are hydrogen or methyl, being the same or different;
wherein Y1 is trans —CH═CH—, —CH2CH2—, cis-CH═CH—, or —C≡C—; and
wherein Z1 is
wherein g is one, 2, or 3.
It is to be understood that, irrespective of whether specifically designated herein, the most active stereoisomers of the prostaglandin compounds are preferred. Typically, the active isomers are known in the art to be those isomers that mimic naturally-occurring prostaglandins.
Any antimicrobial peptide, or protein, that is presently known, or that may be developed in the future, is within the contemplation of the invention for use as the preservative in improved ophthalmic formulations comprising prostaglandins of Formulae I and II. Illustrative antimicrobial peptides are listed in Table 1.
The list of antimicrobial peptides in Table 1 is illustrative only, and is not meant to be exhaustive. In preferred embodiments, the antimicrobial peptides would be soluble in water, or at least easily formulated into dilute aqueous solutions. Particularly preferred antimicrobial peptides are those of human origin, and include lactoferrin and lactoferricin. Other useful antimicrobial peptides include Buforin II, pexiganan, Apidaecin, and Bactenecin, all of which are readily available and can be easily expressed.
Antimicrobial peptides are available commercially from sources such as Magainin Pharmaceuticals, Plymouth Reading, Pa. or Gem Pharmaceuticals, Birmingham, Ala. Antimicrobial peptides can also be obtained by isolation from natural sources, by isolation as recombinant proteins from bacteria, or cultured mammalian or insect cells. Techniques for isolating or culturing antimicrobial peptides are available in the published literature and are known to a person of ordinary skill in the art.
The prostaglandin compounds of the present invention can be synthesized from commercially available starting materials as described in numerous publications known to those of skill in the art. Prostaglandins are also available from commercial sources, such as Cayman Chemical, Ann Arbor, Mich. or Chinoin, Budapest, Hungary. Useful prostaglandin compounds include, but are not limited to, those compounds specifically listed in the examples presented herein, such as 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2α isopropyl ester; fluprostenol 1,15-lactone; 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2α ethyl amide; 13,14-dihydro-Fluprostenol isopropyl ester; 13,14-dihydro-fluprostenol 1,15-lactone; 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2α 1,15-lactone; 13,14-dihydro-17,17,18,18-tetradehydro -PGF2α 1,15-lactone; 13,14-dihydro-16-phenoxy-17,18,19,20-tetranor PGF2α 1,15-lactone; cloprostenol N-ethyl amide. Cayman Chemical, for example, provides the preferred 1,15-lactone forms of PGF2α analogs.
It is, of course, contemplated that a formulation in accordance with the present invention will could include combinations of more than one prostaglandin and/or antimicrobial peptide.
A topical ophthalmic composition or formulation, in accordance with the present invention, broadly comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound having a chemical structure in accordance with Formulae I and/or II in combination with an antimicrobial peptide preservative.
In typical formulations, the carrier for the active agent(s) would be an aqueous solution buffered to physiologically-acceptable pH levels with an acidic or basic pH adjusting agent. Of course, the osmolarity of the solution would be adjusted with osmolarity adjusting agents, such as sodium chloride (NaCl) or potassium chloride (KCl), as is known in the art. Other ingredients, excipients, and additives which may be desirable to use in the ophthalmic preparations of the present invention include anti-oxidants, co-solvents and viscosity building agents.
In forming compositions for topical administration, the prostaglandin compounds of the present invention are generally formulated as between about 0.0001 to about 0.8 percent by weight (wt %) solutions in an aqueous solution buffered to a pH between 4.5 to 8.0 with a suitable buffering agent, and most preferably between 7.0-7.6. The compounds are preferably formulated as between about 0.0003 to about 0.3 wt % and, most preferably, between about 0.003 and about 0.03 wt %.
Ophthalmic products are typically packaged in multidose form, which generally require the addition of preservatives to prevent microbial contamination during use. In accordance with the invention, the formulation preservative is a naturally-occurring or recombinant antimicrobial peptide, including, but not limited to, the antimicrobial peptides listed hereinabove in Table 1, lactoferrin, and lactoferricin. The antimicrobial peptide typically would be employed at a concentration between about 0.001% and 1.0% by weight.
Prostaglandins, and particularly ester or amide derivatives of prostaglandins, typically have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; Tyloxapol®; Cremophor® EL; sodium dodecyl sulfate; glycerol; PEG 400; propylene glycol; cyclodextrins; or other agents known to those skilled in the art. Such co-solvents are typically employed at a concentration between about 0.01% and about 2% by weight.
Viscosity greater than that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the ophthalmic formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a concentration between about 0.01% and about 2% by weight.
The compounds of Formulae I and II are active in lowering the intraocular pressure in humans and other animals and are therefore useful in the treatment of glaucoma and other disorders that cause an increase in intraocular pressure. Therefore, in a method of use aspect of the invention, a therapeutically effective amount of at least one compound having the structure of Formulae I and II are administered to an affected eye to treat increased intraocular pressure in an ophthalmic formulation containing an antimicrobial peptide preservative.
The preferred route of administration is via the topical application of sterile ophthalmic solutions directly into the eye. The dosage range for topical administration is between about 0.1 and 100 micrograms (μg) per eye per day, and is most preferably between 1 and 10 μg per eye per day. While the precise regimen is left to the discretion of the clinician, it is recommended that the resulting solution be topically applied by placing one drop in each eye one or two times a day.
The following Examples are representative of the type of pharmaceutical preparations or formulations in accordance with the principles of the invention and that are contemplated for topical application in the treatment of glaucoma.
Although the invention has been described in terms of specific embodiments and applications, persons skilled in the art can, in light of this teaching, generate additional embodiments without exceeding the scope or departing from the spirit of the claimed invention. Accordingly, it is to be understood that the drawing and description in this disclosure are proffered to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
This application claims the benefit under 35 U.S.C. §119(e) of U.S. Ser. No. 60/367,071 filed on Mar. 21, 2002 which is a continuation-in-part of co-pending U.S. Ser. No. 09/776,574 filed on Feb. 1, 2001. U.S. Ser. No. 09/776,574 is a continuation of U.S. Ser. No. 60/179,508 filed on Feb. 1, 2000. The disclosures of these applications are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US03/08935 | 3/21/2003 | WO | 8/5/2005 |
| Number | Date | Country | |
|---|---|---|---|
| 60367071 | Mar 2002 | US |
