Methods for treating pain associated with chronic pancreatitis

Abstract

The invention relates generally to methods for treating pain associated with chronic pancreatitis in patients. The methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising secretin and a pharmaceutically acceptable carrier.

Claims

1. A method for treating type B pain resulting from chronic pancreatitis in a human patient, comprising the step of administering to a human patient suffering from type B pain resulting from chronic pancreatitis a therapeutically effective amount of a pharmaceutical composition comprising secretin and a pharmaceutically acceptable carrier, wherein said pharmaceutical composition treats said pain resulting from chronic pancreatitis in said human patient; wherein the dosage of secretin administered to said patient in said pharmaceutical composition ranges from 15-20 micrograms per day, and wherein the dosage of secretin administered to said patient in said pharmaceutical composition ranges from 0.05 micrograms secretin per kg of body weight to 0.8 micrograms secretin per kg of body weight.

2. The method of claim 1, wherein the dosage of secretin administered to said patient in said pharmaceutical composition is about 0.4 micrograms secretin per kg of body weight.

3. The method of claim 1, wherein said secretin is a naturally occurring form of secretin.

4. The method of claim 1, wherein said secretin is a synthetic form of secretin.

5. The method of claim 4, wherein said synthetic form of secretin is synthetic porcine secretin.

6. The method of claim 1, wherein said secretin is a genetically recombined form of porcine, bovine, or human secretin.

7. The method of claim 1, wherein said secretin is synthetic human secretin (sHS).

8. The method of claim 1, wherein said administration step comprises intravenous administration.

9. The method of claim 1, wherein said administration step comprises oral administration.

10. 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, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, electrolytes, protamine sulfate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pryrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and combinations thereof.

11. The method of claim 1, wherein said pain is abdominal pain.

12. The method of claim 1, wherein said pharmaceutical composition further comprises one or more excipients selected from the group consisting of water, gelatin, lactose, starch, magnesium stearate, talc, plant oils, gums, alcohol, petroleum jelly, and combinations thereof.

13. The method of claim 1, wherein said pharmaceutical composition further comprises one or more pharmaceutical adjuvants selected from the group consisting of preservatives, stabilizing agents, wetting agents, emulsifying agents, buffers, salts, and combinations thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) The invention will be more fully understood from the following written description and accompanying figures in which:

(2) FIG. 1 is a graph showing primary outcome results for visual analogue scale measurement; and

(3) FIG. 2 is a graph showing the primary outcome results for morphine equivalent dosing.

DETAILED DESCRIPTION OF THE INVENTION

(4) It has now been unexpectedly found that secretin is effective for treating pain associated with chronic pancreatitis (CP).

(5) In accordance with one embodiment of the method of the present invention, treatment for pain associated with chronic pancreatitis includes administering to a patient in need of such treatment a pharmaceutical composition comprising secretin. Patients subjected to the method of the present invention can benefit from the administration of intravenous secretin to help control pain from CP. For patients on opioid analgesics, a benefit of intravenous secretin according to the method of the invention is to decrease their reliance on these medications and offer an improvement in their pain-free quality of life. Additional benefits could also include decreased nausea, decreased vomiting, decreased use of analgesics, more rapid time to resumption of oral intake, decreased length of hospitalization, decreased time to resumption of normal daily activities, and decreased time to return to work.

(6) As indicated above, the present invention is directed to administering a therapeutically effective amount of a pharmaceutical composition comprising secretin and a pharmaceutically acceptable carrier to a patient suffering from pain associated with chronic pancreatitis. Each of these components is discussed in more detail below.

(7) Secretin is a 3055.5 MW (27 amino acid) gastrointestinal peptide hormone originally extracted from the porcine duodenum. The primary action of secretin is to increase the volume and bicarbonate content of pancreatic juice (Gutierrez L V, et al., Gut 13:721-25 (1972); Laugier R, et al., Digestion 54:54-60 (1993); Cavallini G, et al., Dig. Dis. Sci. 37(1):93-96 (1992)). also increases the pancreatic duct diameter (Glaser J, et al., Int. J. Pancreatol. 15:195-200 (1994); Tulassay Z, et al., Gastroenterol. J. 51:47-50 (1991)) and causes sphincter of Oddi relaxation (Geenen J E et al., Gastroenterology 78:317-24 (1980); Laugier R. Endoscopy 26:222-27 (1994)). In the methods of the invention, secretin may be used from any source. Preferably the secretin used in the methods of the present invention is the naturally occurring form, the synthetic form, or the genetically recombined form of porcine, bovine or human secretin. One useful form of naturally occurring human secretin is manufactured by ChiRhoClin, Inc. (Burtonsville, Md.) with the tradename CHIRHOSTIM. One useful form of porcine secretin is manufactured by ChiRhoClin, Inc. (Burtonsville, Md.) and sold under the trade name SECREFLO by Repligen Corporation (Waltham, Mass.). Another useful form of porcine secretin is manufactured by ChiRhoClin, Inc. (Burtonsville, Md.) with the tradename SECREMAX. A useful form of human secretin is manufactured and sold by ChiRhoClin, Inc. under the tradename SECRETIN-HUMAN.

(8) The secretin may be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition. Thus, the pharmaceutical compositions of this invention comprise secretin from any source (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.

(9) The pharmaceutical compositions of this invention may be administered by any route that produces acceptable bioavailability. Suitable administration methods include, but are not limited to, parenteral methods such as intravenous, subcutaneous and intramuscular and per os (by mouth), or sublingual, and transdermal bolus or continuous infusions of secretin may be used. Particularly useful methods of administration in accordance with the method of the invention include oral and intravenous methods. The risks associated with the use of intravenous secretin administration are minor. There has not been any serious reported adverse drug reaction to human secretin stimulation. Rarely, in the thousands of patients who have undergone pancreatic function testing with human secretin, there is flushing of the face with stable vital signs. Therefore, the risk of administrating secretin is minimal. Secretin is also not known to increase the risk of acute pancreatitis episodes in patients with CP and acute recurrent pancreatitis (ARP) not presently having an acute pancreatitis attack. No allergic reactions have been reported with secretin in commercial use although the administration of a test dose 0.2 mcg (0.1 mL) IV is still recommended. No significant hemodynamic effects have been observed following administration of secretin. Otherwise the risks of administering secretin are minimal.

(10) The pharmaceutical compositions of the invention are preferably administered internally, e.g., intravenously, in the form of conventional pharmaceutical preparations, for example in conventional enteral or parenteral pharmaceutically acceptable excipients containing organic and/or inorganic inert carriers, such as water, gelatin, lactose, starch, magnesium stearate, talc, plant oils, gums, alcohol, VASELINE (petroleum jelly), or the like. The pharmaceutical preparations can be in conventional solid forms, for example, tablets, dragees, suppositories, capsules, 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.

(11) The pharmaceutical preparation of the invention should include an amount of secretin effective for preventing pain from chronic pancreatitis. The effective dosage will depend on several factors, including body weight, body mass index, formulation factor, route of administration, age, gender, disease severity, and the like. Suitable dosages may be, for example, in the range of about 2 to 80 micrograms secretin, more preferably of about 8 to about 36 micrograms secretin, and most preferably between 15 and 20 micrograms secretin per dose administered via intravenous bolus. In terms of body weight, suitable dosages of the pharmaceutical composition should include 0.05 g secretin per kg body weight to about 0.8 g secretin per kg body weight. One particularly effective dose is 0.4 g per kg body weight. As will be appreciated by those skilled in the art, multiple doses of secretin may be required to be administered each day over a period of time (for example, a dose of 16 micrograms secretin (approximately 0.2 micrograms per kilogram body weight) intravenously, four times per day for 7 days.

(12) In order to achieve the above dosage ranges, it will be appreciated by those of skill in the art that the amount of secretin used with a particular form of administration will depend on absolute bioavailability of the secretin dosage and the route of administration. For example, a transdermal patch requires approximately 1 mg of secretin to achieve dosages in the above ranges. A nasal spray requires approximately 2 mg secretin per spray in order to achieve the above dosage ranges. A sublingual tablet or film requires approximately 50 mg secretin to achieve the above dosage ranges, and a tablet or capsule requires approximately 100-250 mg secretin per tablet or capsule to achieve the above dosage ranges.

EXAMPLE

(13) The invention is further described by the following Example, 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.

(14) Background and Aims

(15) Type B pain associated with chronic pancreatitis (CP) is often refractory to standard pain treatments. The following Example shows that intravenous secretin infusions can lead to improvements in daily pain, quality of life, and/or opiate use in patients with type B pain from chronic pancreatitis.

(16) Materials and Methods

(17) Patients

(18) All included patients had been diagnosed with chronic pancreatitis (CP) based on standard cross-sectional imaging, endoscopic ultrasound and/or direct pancreatic function testing. Patients were between 18-70 years of age and had not experienced signs or symptoms of acute pancreatitis within 60 days of enrolling in the study. All patients had type B pain from CP as per the definition by Ammann (severe, unremitting pain) and all but one were taking opioids at the time of presentation (Ammann R W et al., Gastroenterology 111:224-231 (1996)). All patients provided written, informed consent. ChiRhoStim (human secretin for injection) was provided by ChiRhoClin Inc. Burtonsville, Md.

(19) Study Design

(20) The study was designed as a single-center, prospective, phase II dose-escalation trial. After initial screening, patients completed a 10 point visual analogue scale assessment of their pain at five time points during one full day prior to human secretin administration (baseline). The SF-36 score was also recorded at baseline. Finally, baseline daily opioid use was calculated and converted to morphine equivalents in milligrams.

(21) Patients were given three intravenous bolus doses of human secretin two hours apart on each day for the first three days of the study. The infusion doses of synthetic human secretin (sHS) per the schedule in Table 1 were based on doses that have been previously reported as safe when used for other purposes (Krishnaswami S, et al., Pediatrics 2011; 127(5):e1322-5.)

(22) TABLE-US-00001 TABLE 1 Study Dosing Schedule and Outcome Assessment Protocol Scheme Intervention Time sHS Dose Visual Analog SF-36 Day 1 Dosing Schedule 0 min 0840 X X Test dose (0.2 mcg) 0859 Dose 1 (0.5 mcg/kg) 0900 X 100 min post Dose 1 1040 X Dose 2 (0.1 mcg/kg) 1100 X 100 min post Dose 2 1240 X Dose 3 (0.2 mcg/kg) 1300 X 100 min post Dose 3 1440 X 380 min post Dose 3 2100 X Day 2 Dosing Schedule 0 min 0840 X Dose 1 (0.1 mcg/kg) 0900 X 100 min post Dose 1 1040 X Dose 2 (0.2 mcg/kg) 1100 X 100 min post Dose 2 1240 X Dose 3 (0.4 mcg/kg) 1300 X 100 min post Dose 3 1440 X 380 min post Dose 3 2100 X Day 3 Dosing Schedule 0 min 0840 X Dose 1 (0.2 mcg/kg) 0900 X 100 min post Dose 1 1040 X Dose 2 (0.4 mcg/kg) 1100 X 100 min post Dose 2 1240 X Dose 3 (0.8 mcg/kg) 1300 X 100 min post Dose 3 1440 X 380 min post Dose 3 2100 X

(23) Patients were blinded to the dose of sHS given, but were told that each administration was a different dose of the medication. After each administration, patients were monitored carefully for any adverse reactions. The primary investigators were blinded to all outcome assessments until the all patients had completed the study.

(24) Outcome Measurements

(25) The primary outcome measurements were the change in baseline VAS score, SF-36 score and opioid use at 30 days post-infusion. Secondary outcomes included any adverse events and the dose at which sHS appeared to be most efficacious.

(26) Adverse Events

(27) Adverse events were reported on an individualized case report form which recorded the adverse reaction, its severity, the likelihood of relationship to the study drug, the action taken and the outcome of the event. Adverse events were recorded from the time of the first sHS administration until 30 days post-administration.

(28) Data Safety Monitoring

(29) The primary investigator was informed of all adverse events as they occurred and completed the adverse events case report forms. An independent reviewer analyzed all of the adverse events and completed the Data Safety Monitoring Report at the conclusion of the study.

(30) Statistics

(31) As this study represents a pilot dose escalation study, the large number of patients normally required to power a standard trial were not utilized. The study was designed with sufficient power to determine a beneficial effect of the study group, for example, a percent improvement following drug administration. Descriptive statistics were used to describe the patient population. Continuous variables were evaluated using the two-tailed students' t-test and dichotomous variables using chi-squared analysis. All statistical evaluation was performed using Microsoft Excel (Redmond, Wash.) and Graphpad (La Jolla, Calif.) software.

(32) Results

(33) Patients

(34) Twelve (12) patients (6 men) were screened and all included in the study after obtaining written, informed consent. The mean age was 42 and average length of pain from CP was 9.5 years (Table 2). All 12 patients received 9 doses of sHS, and 11 patients completed the study (1 withdrew prior to study completion). One patient had Type B pain but was at baseline intolerant of opiods and thus morphine equivalents were not established for this individual.

(35) TABLE-US-00002 TABLE 2 Baseline Patient Characteristics Oral Morphine Years Pain Equivalents SF- Patient Age of CP Gender Cause (VAS) Medications (mg) 36 1 49 9 Female Alcohol 7 Methadone 20 mg, 82.5 101 Oxycodone 5 mg 2 50 8 Male Alcohol 5 Fentanyl 100 mcg/hr 200 106 3 38 7 Female Genetic 7 Morphine 180 mg 180 114 4 40 17 Male Genetic, 7 91 Alcohol 5 56 10 Male Alcohol 8 Methadone 60 mg 225 97 6 29 1 Female Idiopathic 3 Dilaudid 4 mg 16 104 7 42 6 Male Alcohol 6 Methadone 80 mg 300 101 8 38 3 Female Alcohol 4.5 Methadone 30 mg 113 104 9 36 2 Female Alcohol 5 Morphine 75 mg 75 103 10 52 25 Male Alcohol 6 Fentanyl 75 mcg/hr 175 101 Oxycodone 15 mg 11 25 11 Male Idiopathic 4 Morphine 50 mg 50 98 12 50 15 Female Alcohol 7 Morphine 80 mg 80 95 Summary* 42 9.5 6, 6 9 alcohol 5.79 136 101.3 2 genetic 2 idiopathic *Continuous variables represent mean values
Pain

(36) At baseline, patients had a mean VAS of 5.79. On post-treatment days 4, 10, and 30, mean pain scores were 4.80, 4.72, and 4.90 (p=0.25, 0.19, and 0.27 respectively) when compared to baseline. See FIG. 1. In subgroup analysis, females tended to have improved pain compared to males with overall reduction in mean pain from 5.42 at baseline to 3.67 at day 30 (p=0.07). There was no appreciable difference in results when performing subgroup analysis based on age or cause of underlying pancreatitis.

(37) Opiod Usage

(38) At baseline, patients daily opioid usage (oral morphine equivalents) was 136 mg which decreased to 111 mg and 104 mg on days 4 and 30 post-therapy (p=0.52 and 0.34). See FIG. 2. Daily opioid equivalent in females decreased from 107 mg at baseline to 84 mg on Day 30 (p=0.53).

(39) Quality of Life

(40) Quality of life as measured by SF-36 was unaltered with therapy. Mean baseline scores were 101.3, 100.9, and 101.5 at baseline, day 4, and day 30 respectively.

(41) Dosing Optimization

(42) Optimal dosing appears to have been achieved, based on the change in the VAS score, after a dose of 0.4 mcg/kg. See Table 3.

(43) TABLE-US-00003 TABLE 3 Human Secretin Dose-Response Curve Based on Mean VAS 100 sHS dose Pain (g/kg) (VAS 0-10) Baseline 6.04 0.05 4.92 0.1 5.06 0.2 4.92 0.4 4.5 0.8 5.36

CONCLUSIONS

(44) In patients, especially females, with type B pain from chronic pancreatitis requiring high doses of daily opiates, intravenous sHS administration reduced self-reported pain and opiate usage at 30 days post-infusion, although statistical significance was not achieved. These results from this study also support the possibility of central action of secretin on the brain receptors such as VIP receptors in conjunction with opioids use as well as washing the pancreatic ducts with pancreatic fluid from secretin stimulation for reduction in irritation and inflammation of the pancreas due to premature trypsin activation in the pancreatic ducts.

(45) 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.