WO2009089269A1

WO2009089269A1 - Methods of treating pain while minimizing adverse effects on platelet function

Info

Publication number: WO2009089269A1
Application number: PCT/US2009/030311
Authority: WO
Inventors: Robert Colucci; Curtis Wright; Daniel Carr; Karen Ruais
Original assignee: Javelin Pharmaceuticals, Inc.
Priority date: 2008-01-07
Filing date: 2009-01-07
Publication date: 2009-07-16

Abstract

The present invention provides methods of treating pain while minimizing effects on platelet function that include the step of administering to the subject a pharmaceutical composition comprising a diclofenac compound and a beta- cyclodextrin.

Description

METHODS OF TREATING PAIN WHILE MINIMIZING ADVERSE EFFECTS ON PLATELET FUNCTION

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims priority to U.S. Serial No. 61/019,486 filed January 7, 2008 which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions and methods of treating a subject in need of analgesia and at an increased risk of significant blood loss.

BACKGROUND OF THE INVENTION

While effective for pain relief, many analgesics decrease platelet function and thus hinder the ability of blood to clot The analgesic causes an adverse effect on platelet function. Such side-effects prevent the use of analgesics in situations in which there is an increased risk of significant blood loss, such as in a surgical setting or in situations in which a subject is bleeding as a result to a traumatic insult, such as a automobile accident, or a gun shot or knife wound.

In order to safely relieve pain in situations where a subject is at increased risk of substantial blood loss, there remains a need for an analgesic that provides effective pain relief while minimizing a negative effect on platelet function.

SUMMARY OF THE INVENTION

It has been found that pharmaceutical compositions containing a diclofenac compound and a beta-cyclodextrin compound, particularly when parenterally administered, cause less adverse effects on platelet function than other analgesics, including other NSAIDs such as aspirin or ketorolac. Accordingly, the present invention provides methods of treating pain while minimizing effects on platelet function, including methods of treating pain in particular situations in which proper platelet function is crucial. One aspect of the present invention provides a method of treating pain in a subject that includes ^identifying the subject as being at increased risk of significant blood loss and administering a pharmaceutical composition containing a diclofenac compound and a beta-cyclodextrin compound to the subject. Subjects at increased risk of significant blood loss include, but are not limited to, patients who have undergone a surgical procedure, women in labor, subjects who are bleeding as a result of a traumatic insult, hemophiliacs, subjects who have a disorder of coagulation caused by a genetic defect or resulting from an exogenous agent such as, but not limited to, heparin, aspirin, Coumadin, tissue plasminogen activator, streptokinase, etc., and (e.g. a gun-shot wound). Accordingly, embodiments of the present invention provide a method of treating pain attendant to, or caused by, a surgical procedure, childbirth, or pain associated with a traumatic insult to the body. Other embodiments of the present invention provide a method of treating pain in hemophiliacs, and subjects affected by thrombocytopenia (for example, autoimmune thrombocytopenia or thrombocytopenia caused by cancer chemotherapy).

In particular embodiments, each of the methods described herein also include the implementation of other blood-loss control efforts (besides the selection of a diclofenac compound over other analgesics), such as monitoring platelet function, administering a second therapeutic agent to improve platelet functioning, measuring clotting parameters such as prothrombin time ("PT") and/or partial thromboplastin time ("PTT"), and/or applying pressure to the source of the blood loss.

In one embodiment, the pharmacuetical composition containing a diclofenac compound and a beta-cyclodextrin compound (e.g. 2-hydroxypropyl beta- cyclodextrin) is administered parenterally (e.g. intravenously), hi particular embodiments, the amount of diclofenac compound present in the parenterally administered unit dosage may range, for example, from about 9.4 mg to about 75 mg, or from about 18.75 mg to about 50 mg.

Another aspect of the present invention provides a kit for treating subjects at increased risk of significant blood loss that includes a parenteral unit dosage form comprising a diclofenac compound and a beta-cyclodextrin and instructions to administer the parenteral dosage form to subjects at increased risk of significant blood loss. The kit may also contain a second therapeutic agent designed to improve platelet function, either in a second unit dosage form, or combined in one unit dosage form with the dicylofenac compound and beta-cyclodextrin compound. The kit may be provided to nurses and other medical personnel to be used to treat post-operative pain or by emergency medical technicians for use in the treatment of pain in situtations where it is necessary or desireable to minimize blood loss, such as, for example, the treatment of pain resulting from traumatic insults such as gun-shot or knife wounds.

DESCRIPTION OF THE FIGURES

Figure 1 shows the increase from baseline of PFA-100 closure time (measured in seconds) from male blood samples 0-24 hours after administration of one of the four pharmaceutical formulations described in Example 1. Collagen + ADP was used to stimulate clotting in the PFA-100 apparatus.

Figure 2 shows the increase from baseline of PFA-100 closure time (measured in seconds) from male blood samples 0-24 hours after administration of one of the four pharmaceutical formulations described in Example 1. Collagen + epinephrine was used to stimulate clotting in the PFA-100 apparatus.

Figure 3 shows the mean area under the PFA closure time difference curve shown in Figure 1 over six hours (collagen + ADP).

Figure 4 shows the mean shows the mean area under the PFA closure time difference curve shown in Figure 2 over six hours (collagen + epinephrine).

Figure 5 shows the mean area under the PFA closure time difference curve shown in Figure 1 over twelve hours (collagen + ADP).

Figure 6 shows the mean area of the PFA closure time difference curve shown in Figure 2 over twelve hours (collagen + epinephrine).

DETAILED DESCRIPTION OF THE INVENTION

The term "diclofenac compound" refers to diclofenac or a pharmaceutically acceptable diclofenac salt. A pharmaceutically acceptable salt of diclofenac can be an alkali metal salt, for example the sodium or the potassium salt, or the salt formed with an amine, e.g., a mono-, di- or tri- Ci-C₄ alkylamine, for example diethyl- or triethyl-amine, hydroxy-C₂-C₄ alkylamine, for example ethanolamine, or hydroxy-C₂-C4 alkyl-Ci-C₄ alkylamine, for example dimethylethanolamine, or a quaternary ammonium salt, for example the tetramethylammonium salt or the choline salt of diclofenac (see, e.g., U.S. Patent No. 5,389,681). Preferably the diclofenac salt is diclofenac sodium.

Formulations of the present invention for parenteral administration include cyclodextrin inclusion complexes. One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility and efficacy of compounds of the present invention. Useful cyclodextrins for this purpose include beta-cyclodextrins and derivatives of beta-cyclodextrins, such as hydroxyalkyl ether derivatives (e.g. 2-hydroxy propyl β-cyclodextrin).

The term "beta-cyclodextrin" as used herein refers to cyclic alpha- 1,4- linked oligosaccharides of a D-glucopyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface, and derivatives thereof. Particular efficacy has been observed in the present invention utilizing hydroxypropyl-beta- cyclodextrin, however, other substituted and unsubstituted β-cyclodextrins can also be used in the practice of the invention. Additional examples of cyclodextrins that may be utilized are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604, 5,024,998, 6,407,079, 6,828,299, 6,869,939 and Jambhekar et al., 2004 Int. J Pharm. 2004, 270(1-2) 149-66, all of which are hereby incorporated by reference. The formulations may be prepared as described in U.S. Patent Nos. 5,679,660 and 5,674,854, all of which are hereby incorporated by reference. The "pharmaceutical compositions" for use in accordance with the present invention can be formulated in any conventional manner using one or more pharmaceutically acceptable carriers or excipients. A "pharmaceutically acceptable" carrier or excipient, as used herein, the term "pharmaceutically acceptable" means tolerated by a subject to whom it is administered without causing and untoward reaction and preferably refers to compositions approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in mammals, and more particularly in humans.

Pharmaceutical compositions may include solid dosage forms, e.g., for perioral or buccal (mucoadhesive tabs or solid dosage forms), transnasal (e.g. powder), or rectal (e.g. suppository) administration; and liquid dosage forms, e.g., for parenteral administration (injection), transnasal (spray), perioral administration (e.g. sprays) or ocular (e.g. eye drops). In a specific embodiment, the pharmaceutical compositions of the present invention are liquid compositions formulated for intravenous or intramuscular administration, and particularly intravenous administration.

As used herein, the term "stabilizer" refers to a compound optionally used in the pharmaceutical compositions of the present invention in order to avoid the need for sulphite salts and increase storage life. Optimal stabilizers include antioxidants, specifically monothioglycerol and those described in U.S. Patent Publication 2005/0238674, which is hereby incorporated by reference.

Unless indicated otherwise, dosage amounts express the amount (e.g. the weight) of diclofenac compound contained in the unit dosage form. The term "mammal" is intended to include, any warm-blooded vertebrate having the skin more or less covered with hair. Most preferably, the mammal is a human subject, but the mammal can also be a non-human animal. Thus, the invention is useful in veterinary medicine as well, e.g., for treating pain in a domestic pet, such as a canine or feline, a farm animal, a work animal, or an animal in a circus or zoological garden in situations where it is desireable to minimize adverse effects on platelet function.

In one embodiment of the present invention the subject to whom the pharmaceutical composition containing a diclofenac compound and beta-cyclodextrin is administered is a mammal. In a preferred embodiment, the subject is a human. The term "minimum approved dose" refers to the minimum dosage that has received full regulatory approval by the appropriate United States or foreign regulatory authority as safe and effective for human or veterinary use.

The term "therapeutically effective" as applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a analgesia upon administration to a mammal in need thereof.

The term "amount" as used herein refers to quantity or to concentration as appropriate to the context. In the present invention, the effective amount of a compound refers to an amount sufficient to treat a patient/subject in need of analgesia. The effective amount of a drug that constitutes a therapeutically effective amount varies according to factors such as the potency of the particular drug, the route of administration of the formulation, and the mechanical system used to administer the formulation. A therapeutically effective amount of a particular drug can be selected by those of ordinary skill in the art with due consideration of such factors. The term "significant blood loss" as used herein refers to an amount of blood loss that would cause, or would be likely to cause, deleterious effects (e.g. clinical sequela) on the subject, i.e., Class II, III or IV hemorrhage as defined by the American College of Surgeons' Advance Trauma Life Support (ATLS). Such deleterious effects include, but are not limited to, one of more of the following conditions that occur as a result of the blood loss: hypovolemia, hypotension, fainting, shock, tachycardic (rapid heart beat), vacoconstriction, cardiac repression and death. As used herein, "significant blood loss" typically refers to loss of 15% or more of blood volume, although it is understood that less than 15% blood loss may be considered significant in patients with reduced ability to tolerate blood loss (e.g. the elderly, or subjects with chronic medical conditions).

A subject that is part of a sub-population at increased risk of significant blood loss may be part of such a sub-population by virtue of a pre-existing condition (e.g. hemophilia or thrombocytopenia (low platelet count)) or by virtue of the nature of the injury that causes pain. Non-limiting examples of subjects that are part of a sub-population at increased risk of significant blood loss includes subjects undergoing, or having undergone surgery, subjects currently under anticoagulant medication such as warfarin, heparin or beta-blockers, women in labor (childbirth), patients who have experienced a trauma, such as but not limited to, gunshot wounds, crushing injuries, contusions, puncture wounds, incisions, and lacerations.

The term "hemophilia" refers to any condition which impairs the ability of blood to clot or coagulate and includes hemophilia A, hemophilia B and hemophilia C.

As noted throughout this application, diclofenac formulations containing a beta-cyclodextrin (e.g. hydroxypropyl beta-cyclodextrin) have been found to minimize adverse platelet function. While decreased blood clotting is favorable, and not adverse, in other contexts (e.g. patients at risk of, or currently having a heart attack, thrombosis or stroke) it is understood that minimizing adverse platelet function as used herein refers to minimizing blood loss and minimizing the decreased blood clotting that is often attendant to analgesic treatment, such as treatment with ketorolac and aspirin.

The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5 -fold, and more preferably within 2-fold, of a value.

As used herein, the term "treat" or "treating" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" or "treating" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

Methods of Treatment As noted above, the present invention provides methods of treating pain, i.e., for analgesia, while minimizing adverse platelet function that includes the step of administering a pharmacuetical composition containing a diclofenac compound and a beta-cyclodextrin (e.g. hydroxypropyl beta-cyclodextrin). Embodiments of the present invention provides methods of treating pain in sub- populations at risk of significant blood loss and includes methods of treating pain in any of the subject sub-populations described in this application. Accordingly, the present invention provides methods of treating pain before or after surgery (e.g. postoperative pain), methods of treating pain associated with childbirth, methods of treating pain in subjects inflicted with hemophilia or with low or impaired platelet count, and methods of treating pain in subjects whose pain is due to a trauma (e.g. gunshot or knife wound).

The formulations of the invention are suitable for treating pain by administration either or both prophylactically and after onset of the pain. Thus, as used herein, the term "treat" (in any of its grammatical forms) means to reduce pain through administration of a formulation of the invention prior to or after the onset of pain, or both. In particular, the formulations are suitable in the treatment of acute painful conditions in humans and animals such as headache, including migraine, trauma, dysmenorrhoea, renal or biliary colic, post-operative pain, gout, arthritis, cancer related pain, musculoskeletal pain, lower back pain, fibromyalgia, and pain of infectious origin. Indeed, the low dosage of diclofenac will have little or no anti- inflammatory activity, so in the treatment of pain of infectious origin it will have little effect on any immune response to the infectious organism while achieving analgesia. In a specific embodiment the formulation is effective to treat post-surgical dental pain resulting from surgical extraction of one or more third molars, hi addition, although not intending to be bound by any particular mechanism of action, the formulation of the invention may be used prophylactically to prevent the formation of prostaglandins during and after surgery, with subsequent reduction in immediate post-operative pain. Further, the formulation of the invention may be used to modulate nuclear transcription factors, such as NF-κB, or to modulate ion channel activity, for example as described in Ocana, Maria et al., Potassium Channels and Pain: Present Realities and Future Opportunities, 500 Eur. J. Pharm. 203 (2004).

Dosage Form and Dosage Amounts

The pharmaceutical compositions containing a diclofenac compound and a beta-cyclodextrin may be administered in any dosage form in which pharmaceutical compositions may be administered (e.g. a solid or liquid oral dosage forms) and may be administered in any amount deemed effective for treating pain. While not being bound thereby, it is believed that pharmaceutical compositions containing a beta-cyclodextrin and a low dose of diclofenac compound (i.e., less than 75 mg of diclofenac compound) administered parenterally minimize adverse platelet function to a greater extent as compared to other analgesics and other formulations of diclofenac. Accordingly, in one embodiment of the present invention, the pharmaceutical compositions used in the methods of the present invention is administered parenterally (e.g. intravenously) with low diclofenac compound dosage amounts, i.e. from about 9.4 mg to about 75 mg, or from about 18.75 mg to about 50 mg (e.g. 37.5 mg) of diclofenac compound per unit dose. Alternatively, any of the dosage amounts of diclofenac compound disclosed in U.S. Published Application No. 2007/0232566, which is hereby incorporated by reference, may be employed. In one embodiment of the present invention, the diclofenac compound is administered via any route except rectal administration.

In one embodiment the amount of diclofenac compound is less than 2 mg/kg of body weight. In one embodiment the amount of diclofenac compound is not 2 mg/kg of body weight.

EXAMPLES

The present invention will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

EXAMPLE 1: Analysis of Platelet Function in Healthy Males Following Administration of Analgesics

An open-label, randomized, single-dose, four treatment crossover study was performed to evaluate the platelet function in healthy males following a single dosage of the following compositions:

(a) a single bolus intravenous injection of 1 ml of a liquid formulation containing 37.5 mg of diclofenac sodium (complete composition shown below in Table 1);

(b) 50 mg of Cataflam^®, a solid oral dosage form containing diclofenac potassium;

(c) 30 mg of intravenously administered ketorolac tromethamine; and

(d) 325 mg of orally administered aspirin. The complete formulation of the intravenous injection of the liquid formulation containing diclofenac sodium is shown below in Table 1 :

Table 1

Thirty healthy male subjects received one dose of each study drug, with a 48-hour washout period between successive treatments. Platelet function was ascertained by a adding blood samples to a PFA- 100™ platelet analyzer using collagen-ADP cartridge or a collagen-epinephrine cartridge to stimulate clotting. The platelet function analysis technique using the PFA- 100™ system is described in greater detail in "Seminars in Thrombosis and Hemostasis", Vol. 24, No. 2 (1998), pp. 195-202 which is hereby incorporated by reference.

Increase in closure time from baseline over 24 hours is charted in Figure 1 (collagen + ADP) and Figure 2 (collagen+epinephrine). Figures 3-6 show the area under these curves over 6 hours (Figures 3 and 4) and 12 hours (Figures 5 and 6).

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Patents, patent applications publications product descriptions, and protocols are cited throughout this application the disclosures of which are incorporated herein by reference in their entireties for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of treating pain in a subject comprising identifying the subject as being at increased risk of significant blood loss and administering to the subject a pharmaceutical composition comprising a diclofenac compound and a beta- cyclodextrin.

2. The method of claim 1, wherein the diclofenac compound is administered parenterally.

3. The method of claim 2, wherein the amount of diclofenac compound administered to the subject ranges from about 9.4 mg to about 75 mg.

4. The method of claim 3, wherein the amount of diclofenac compound administered to the subject ranges from about 18.75 mg to about 50 mg.

5. The method of claim 4, wherein the beta-cyclodextrin is hydroxypropyl beta cyclodextrin.

6. The method of claim 5 wherein the diclofenac compound is diclofenac sodium.

7. The method of claim 6, wherein the pharmaceutical composition further comprises an antioxidant.

8. The method of claim 7, wherein the antioxidant is monothio glycerol.

9. The method of claim 1, wherein the pain is post-operative pain.

10. The method of claim 1, wherein the pain is pain attendant to childbirth.

11. The method of claim 1, wherein the pain is pain resulting from a trauma.

12. The method of claim 11 wherein the pain resulting from a trauma is pain resulting from a gunshot or knife wound.

13. The method of claim 1 wherein the subject has hemophilia.

14. The method of claim 1 wherein the subject has thrombocytopenia.

15. The method of claim 1 wherein the subject is currently under anticoagulant medication.

16. A method of treating pain in a subj ects at increased risk of significant blood loss comprising:

(a) parenterally administering to the subject a pharmaceutical composition comprising a beta-cyclodextrin and from about 9.4 mg to about 75 mg of a diclofenac compound; and

(b) implementing blood-loss control efforts.

17. The method of claim 16 wherein the blood-loss control efforts include monitoring platelet function.

18. The method of claim 16 wherein the blood-loss control efforts include applying pressure and/or a material to the source of the blood loss.

19. The method of claim 16, wherein the pharmaceutical composition contains from about 18.75 mg to about 50 mg of diclofenac compound

20. A kit for treating pain in subjects at increased risk of significant blood loss comprising:

(a) a parenteral unit dosage form comprising a beta-cyclodextrin and from about 9.4 mg to about 75 mg of a diclofenac compound; and (b) instructions to administer the parenteral dosage form to subjects at increased risk of significant blood loss.