METHODS FOR TREATING POST ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY PANCREATITIS

Abstract

This invention relates generally to methods of treating post-endoscopic retrograde cholangiopancreatography pancreatitis. The method comprises sublingually or buccally administering to a patient deemed to be at risk of developing post endoscopic retrograde cholangiopancreatography pancreatitis prior to undergoing endoscopic retrograde cholangiopancreatography (ERCP), a therapeutically effective amount of a pharmaceutical composition comprising indomethacin or diclofenac or a combination thereof and a pharmaceutically acceptable carrier.

Claims

1. A method of treating post-endoscopic retrograde cholangiopancreatography pancreatitis, the method comprising the step of sublingually or buccally administering to a patient deemed to be at risk of developing post endoscopic retrograde cholangiopancreatography pancreatitis prior to undergoing endoscopic retrograde cholangiopancreatography (ERCP), a therapeutically effective amount of a pharmaceutical composition comprising indomethacin or diclofenac or a combination thereof and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein the method comprises the step of sublingual administration.

3. The method of claim 1, wherein the method comprises the step of buccal administration.

4. The method of claim 1, wherein the amount of indomethacin or diclofenac or combination thereof administered to said patient in said pharmaceutical composition ranges from about 1 to about 500 milligrams.

5. The method of claim 1, wherein the amount of indomethacin or diclofenac or combination thereof administered to said patient in said pharmaceutical composition ranges from about 25 to about 250 milligrams.

6. The method of claim 1, wherein the amount of indomethacin or diclofenac or combination thereof administered to said patient in said pharmaceutical composition ranges from about 50 to about 150 milligrams.

7. The method of claim 1, wherein said pharmaceutically acceptable carrier is selected from the group consisting of ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride (saline), zinc salts, colloidal silica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and combinations thereof.

8. The method of claim 1, wherein said patient is a human.

9. A method for treating post-endoscopic retrograde cholangiopancreatography pancreatitis, consisting of the step of sublingually or buccally administering to a patient deemed to be at risk of developing post endoscopic retrograde cholangiopancreatography pancreatitis prior to undergoing endoscopic retrograde cholangiopancreatography (ERCP), a pharmaceutical composition comprising from about 1 to about 500 milligrams of indomethacin or diclofenac or a combination thereof and a pharmaceutically acceptable carrier, wherein said pharmaceutical composition is effective for reducing the incidence of post endoscopic retrograde cholangiopancreatography pancreatitis; and wherein said pharmaceutical composition is administered before any cannulation procedures.

10. The method of claim 9, wherein the method comprises the step of sublingual administration.

11. The method of claim 9, wherein the method comprises the step of buccal administration.

12. The method of claim 9, wherein said pharmaceutically acceptable carrier is selected from the group consisting of ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride (saline), zinc salts, colloidal silica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and combinations thereof.

13. The method of claim 9, wherein the amount of indomethacin or diclofenac or combination thereof administered to said patient in said pharmaceutical composition ranges from 25 to about 250 milligrams.

14. The method of claim 9, wherein the amount of s indomethacin or diclofenac or combination thereof administered to said patient in said pharmaceutical composition ranges from about 50 to about 150 milligrams.

15. The method of claim 9, wherein said patient is a human.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0026] It has now been unexpectedly found that sublingual or buccal administration of indomethacin or diclofenac or a combination thereof is effective for treating or modulating the severity of post endoscopic retrograde cholangiopancreatography pancreatitis (post-ERCP pancreatitis). The treatment includes sublingually or buccally administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising indomethacin or diclofenac or a combination thereof and a pharmaceutically acceptable carrier prior, during, or immediately after ERCP is performed on that patient. Sublingual and buccal routes of administration of indomethacin or diclofenac or a combination thereof for treatment of conditions such as post-ERCP pancreatitis or other forms of pancreatitis or anti-inflammatory conditions, offers the advantage of fast and effective relief for these painful conditions, as well as the avoidance of unwanted side effects which can be a dangerous, or deadly affliction, during the ERCP procedure. Without wishing to be bound by any particular theory, it is believed that sublingual or buccal administration allows for indomethacin or diclofenac or a combination thereof to enter into the bloodstream directly and thereby bypass the gastrointestinal (GI) tract of the patient. In doing so, the indomethacin or diclofenac is not exposed to the body's digestive and filtering mechanisms such as found in the stomach and liver which would break down the indomethacin and reduce its effectiveness.

[0027] As indicated above, in one aspect, the present invention is directed to a method of treating post-endoscopic retrograde cholangiopancreatography pancreatitis, the method comprising the step of sublingually or buccally administering to a patient deemed to be at risk of developing post endoscopic retrograde cholangiopancreatography pancreatitis prior to undergoing endoscopic retrograde cholangiopancreatography (ERCP), a therapeutically effective amount of a pharmaceutical composition comprising indomethacin or diclofenac or a combination thereof and a pharmaceutically acceptable carrier. Each of these components and steps is explained in more detail below.

[0028] Indomethacin is a known and potent synthetic nonsteroidal indole derivative with anti-inflammatory activity and chemopreventive properties. Indomethacin is used to relieve pain, swelling, and joint stiffness caused by arthritis, gout, bursitis, tendonitis, and various other conditions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potent inhibitors of phospholipase A2, cyclooxygenase, and neutrophil-endothelial interactions, that are believed to play an important role in the pathogenesis of acute pancreatitis (Elmunzer B J, et al N. Engl. J. Med. 2012; 366:1414-1422). Meta-analysis of preliminary studies evaluating the protective effects of single-dose rectal indomethacin or diclofenac in post-ERCP pancreatitis have suggests benefit.

[0029] Diclofenac, sold under the brand name Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. The primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2) also known as cyclooxygenase-2 (COX-2).

[0030] Indomethacin or diclofenac may be used individually or in a suitable combination, and combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition. Thus, the pharmaceutical compositions of this invention comprise indomethacin from any source outlined above (including pharmaceutically acceptable salts thereof) in combination with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride (saline), zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0031] The indomethacin or diclofenac compounds of the invention are preferably administered either individually or in combination in a sublingual or buccal form and in an amount that produces acceptable bioavailability. In one embodiment, the compounds are administered preferably in a neat form or in a form of conventional pharmaceutical preparations, for example, in conventional water soluble pharmaceutically acceptable excipients containing organic and/or inorganic inert carriers, such as water, gelatin, saccharides, lactose, starch, magnesium stearate, talc, plant oils, gums, alcohol, Vaseline, or the like. Examples of some suitable disintegrator excipients are, croscarmellose sodium, sodium starch glycolate, and crospovidone. The non-limiting examples of some suitable pH adjusting excipients are sodium bicarbonate (NaHCO.sub.3), calcium carbonate (CaCO.sub.3), Na.sub.2CO.sub.3 (an alkalizing agent), and poloxamer 407 (a polymer used in the formulation of a nano-emulsifying solid dispersion formulations). Amorphous solid distribution carrier matrix materials such as PVP (polyvinyl pyrrolidone), HPMC (hydroxypropyl methylcellulose), HPMCP (hydroxypropyl methylcellulose phthalate), chitosan, CMC (carboxymethylcellulose), sodium alginate and sodium starch glycolate. The pharmaceutical preparations can be in conventional solid forms, for example, tablets, films, sprays, dragées, suppositories, capsules, amorphous solid dispersions, or the like, or conventional liquid forms, such as suspensions, emulsions, or the like. If desired, they can be sterilized and/or contain conventional pharmaceutical adjuvants, such as preservatives, stabilizing agents, wetting agents, emulsifying agents, buffers, or salts used for the adjustment of osmotic pressure. The pharmaceutical preparations may also contain other therapeutically active materials.

[0032] The pharmaceutical preparation of the invention should include an amount of indomethacin effective for preventing acute pancreatitis. In one embodiment, indomethacin, diclofenac, a combination thereof, or a pharmaceutical preparation of it, would be administered as soon after diagnosis of acute pancreatitis as possible and given daily (in divided doses) for about 3 days to about 14 days. The effective dosage will depend on several factors, including body weight, body mass index, age, gender and disease severity. Suitable dosages may be, for example, in the range of about 1-500 milligrams, or about 25 to about 250 milligrams, or about 50 to about 150 milligrams per dose. In addition, multiple doses of indomethacin and/or diclofenac may be required to be administered each day over a period of sublingually or buccally, up to four times per day for 7 days or more.

Examples

[0033] The invention is further described by the following Examples, but is not intended to be limited by the Examples. All parts and percentages are by weight and all temperatures are in degrees Celsius unless explicitly stated otherwise.

[0034] The compositions and methods of the present invention are intended to preemptively treat patients at high or average risk of post-ERCP pancreatitis. As such, the compositions of the invention are intended to be administered either before or immediately following pancreatic surgery.

[0035] In one embodiment, an appropriate sublingual or buccal composition containing appropriate amounts of indomethacin, diclofenac or a combination thereof (generally ranging from 1-500 mg) is made using conventional production techniques known to those of skill in the art. The sublingual or buccal composition containing indomethacin, diclofenac, or a combination thereof is preferably administered to a human patient through a sublingual or buccal route prior to or immediately following pancreatic surgery. Administration may follow the following regimen: 1-500 mg two times a day, or 25-250 mg four times a day, or 50-150 mg four times a day.

Patient Evaluation

[0036] The change in biochemical parameters that represent local and systemic effects of acute pancreatitis will be monitored, including changes from baseline values of C− reactive protein, pancreatic enzymes, sedimentation rate, hematocrit, APACHE II score, and oxygen saturation. Continuous monitoring of vital signs per standard of care and adverse events will also be monitored. Abdominal pain, elevated levels of amylase and lipase, inflammation, and fever are cardinal symptoms of pancreatitis and will be monitored and treated based on standard practice guidelines. Vital signs will be recorded at baseline prior to administration of study medication (indomethacin) and continuously throughout the study period per standard of care. A successful outcome will be indicated by no evidence of post-ERCP pancreatitis, or a reduction in symptoms, such as abdominal pain, elevated levels of amylase and lipase, inflammation, and fever.

[0037] While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents, and other publications cited herein are incorporated by reference in their entireties.