METHODS AND COMPOSITIONS FOR THE TREATMENT OF SYMPTOMS OF COMPLEX REGIONAL PAIN SYNDROME

Abstract

A therapeutic composition for the treatment of the symptoms of complex regional pain syndrome and the method for preparing the therapeutic agents is disclosed. The therapeutic composition is a stable pharmaceutical composition comprising one or more digestive and/or pancreatic enzymes. The therapeutic composition may be manufactured by a variety of encapsulation technologies. Delivery of the therapeutic composition may be made orally, through injection, by adherence of a medicated patch or other method. Further, a method of using fecal chymotrypsin level as a biomarker for the presence of complex regional pain syndrome, or the likelihood of an individual to develop complex regional pain syndrome is disclosed.

Claims

1. A method for treating one or more symptoms associated with Complex Regional Pain Syndrome in a patient diagnosed with Complex Regional Pain Syndrome comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising one or more digestive enzymes.

2. The method of claim 1 wherein the one or more digestive enzymes comprise one or more enzymes selected from the group consisting of proteases, amylases, celluloses, sucrases, maltases, papaya, papain, and lipases.

3. The method of claim 1 wherein the one or more digestive enzymes comprise one or more pancreatic enzymes.

4. The method of claim 2 wherein the proteases comprise chymotrypin and trypsin.

5. The method of claim 1 wherein the one or more digestive enzymes are, independently, derived from an animal source, a microbial source, or a plant source, or are synthetically prepared.

6. The method of claim 5 wherein the animal source is a pig.

7. The method of claim 1 wherein the pharmaceutical composition comprises at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain.

8. The method of claim 7 wherein the pharmaceutical composition further comprises papaya.

9. The method of claim 1 wherein the pharmaceutical composition comprises: amylases from about 10,000 to about 60,000 U.S.P, proteases from about 10,000 to about 70,000 U.S.P, lipases from about 4,000 to about 30,000 U.S.P, chymotrypsin from about 2 to about 5 mg, trypsin from about 60 to about 100 mg, papain from about 3,000 to about 10,000 USP units, and papaya from about 30 to about 60 mg.

10. The method of claim 1 wherein the pharmaceutical composition comprises at least one protease and at least one lipase, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1.

11. The method of claim 10 wherein the ratio of proteases to lipases ranges from about 4:1 to about 10:1.

12. The method of claim 1 wherein the one or more symptoms of Complex Regional Pain Syndrome are selected from intense pain, a burning sensation, skin sensitivity, changes in skin temperature, color or texture, changes in hair and nail growth, joint stiffness, swelling and damage, muscle spasms, muscle weakness, muscle loss (atrophy), and decreased ability to move an affected body part.

13. The method of claim 1 wherein the pharmaceutical composition is a dosage formulation selected from the group consisting of: pills, tablets, capsules, microcapsules, mini-capsules, time released capsules, mini-tabs, sprinkles, and a combination thereof. Complex Regional Pain Syndrome.

14. A method of diagnosing a patient comprising: obtaining a fecal sample from the patient; determining a level of chymotrypsin present in the fecal sample; and diagnosing the patient as having Complex Regional Pain Syndrome if the determined fecal chymotrypsin level is 8.4 U/gram or less and the patient exhibits at least one symptom associated with.

15. The method of claim 14 wherein the fecal chymotrypsin level is between 8.4 and 4.2 U/gram.

16. The method of claim 14 wherein the fecal chymotrypsin level is less than 4.2 U/gram.

17. The method of claim 14 wherein the level of chymotrypsin present in the fecal sample is determined using an enzymatic photospectrometry method.

18. The method of claim 14 further comprising administering to the patient an effective amount of a pharmaceutical composition comprising one or more digestive enzymes if the patient is diagnosed as having Complex Regional Pain Syndrome.

19. The method of claim 18 further comprising determining if the administration of the pharmaceutical composition reduces one or more symptoms associated with Complex Regional Pain Syndrome.

20. The method of claim 19 further comprising comparing the post-administration measurement of one or more Complex Regional Pain Syndrome symptoms to a pre-administration measurement of the one or more Complex Regional Pain Syndrome symptoms.

21. A method of identifying a patient likely to benefit from administration of a pharmaceutical composition comprising one or more digestive enzymes comprising: obtaining a fecal sample from the patient; determining a level of chymotrypsin present in the fecal sample; and identifying the patient as likely to benefit from administration of the pharmaceutical composition if the determined fecal chymotrypsin level is 8.4 U/gram or less and the patient is diagnosed with Complex Regional Pain Syndrome.

22. The method of claim 21 further comprising determining if the patient exhibits one or more symptoms of Complex Regional Pain Syndrome.

23. The method of claim 21 wherein the benefit comprises a reduction in one or more symptoms associated with Complex Regional Pain Syndrome.

24. The method of claim 21 wherein the level of chymotrypsin present in the fecal sample is determined using an enzymatic photospectrometry method.

25. The method of claim 21 further comprising administering to the patient an effective amount of a pharmaceutical composition comprising one or more digestive enzymes.

26. A pharmaceutical composition comprising one or more digestive enzymes, wherein the one or more digestive enzymes comprise at least one lipase and at least one protease, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1.

27. The pharmaceutical composition of claim 26 wherein the ratio of total proteases to total lipases ranges from about 4:1 to about 10:1.

28. A pharmaceutical composition comprising at least one amylase, a mixture of proteases comprising chymotrypsin and trypsin, at least one lipase, and papain.

29. The pharmaceutical composition of claim 28 wherein the pharmaceutical composition further comprises papaya.

30. The pharmaceutical composition of claim 28 wherein the ratio of total proteases to total lipases ranges from about 1:1 to about 20:1.

31. A pharmaceutical preparation for treating an individual exhibiting one or more symptoms of complex regional pain syndrome comprising a therapeutically effective amount of a digestive enzyme.

32. The pharmaceutical preparation of claim 31 wherein the digestive enzyme is selected from the group consisting of: amylase, lipase, protease, and a combination thereof.

33. The pharmaceutical preparation of claim 31 wherein the digestive enzyme is further selected from the group consisting of: chymotrypsin, trypsin, papaya, papain, and a combination thereof.

34. The pharmaceutical preparation of claim 31 wherein the enzyme is derived from a source selected from the group consisting of animal enzymes, plant enzymes, synthetic enzymes, and a combination thereof.

35. The pharmaceutical preparation of claim 31 wherein the preparation is manufactured using a technology selected from the group consisting of Prosolv technology, enteric coating, lipid encapsulation, direct compression, dry granulation, wet granulation, and a combination thereof.

36. The pharmaceutical preparation of claim 31 wherein the preparation is administered orally via a dosage formulation selected from the group consisting of: pills, tablets, capsules, microcapsules, mini-capsules, time released capsules, mini-tabs, sprinkles, and a combination thereof.

37. The pharmaceutical preparation of claim 32 wherein the amount of amylase ranges from 10,000 to 60,000 USP units/mg.

38. The pharmaceutical preparation of claim 32 wherein the amount of protease ranges from 10,000 to 70,000 USP units/mg.

39. The pharmaceutical preparation of claim 32 wherein the amount of lipase ranges from 4,000 to 30,000 USP units/mg.

40. The pharmaceutical preparation of claim 33 wherein the amount of pancreatin ranges from 2,000 to 6,000 USP units/mg.

41. The pharmaceutical preparation of claim 33 wherein the amount of chymotrypsin ranges from 2 to 5 mg.

42. The pharmaceutical preparation of claim 33 wherein the amount of papain ranges from 3,000 to 10,000 USP units/mg.

43. The pharmaceutical preparation of claim 33 wherein the amount of papaya ranges from 30 to 60 mg.

44. The pharmaceutical preparation of claim 33 wherein the amount of trypsin ranges from 60 to 100 mg.

45. The pharmaceutical preparation of claim 31 wherein a symptom of the complex regional pain syndrome is ameliorated.

46. The pharmaceutical preparation of claim 31 wherein the symptom of the complex regional pain syndrome is selected from the group consisting of: pain, skin sensitivity, changes in skin temperature, color and texture, changes in hair and nail growth, joint stiffness, swelling and damage, muscle spasms, weakness and atrophy, decreased ability to move an affected body part, and a combination thereof.

47. A method of treating an individual having Complex Regional Pain Syndrome with a therapeutically effective amount of digestive enzymes comprising the steps of: measuring a level of fecal chymotrypsin in a stool sample of the individual; comparing the level of fecal chymotrypsin with a normal fecal chymotrypsin level; and administering the digestive enzymes to the individual if the level of fecal chymotrypsin in the individual is less than the normal fecal chymotrypsin level.

48. The method of claim 47 further comprising the steps of: administering the digestive enzymes to the individual in order to promote protein digestion; and administering the digestive enzymes to the individual in order to ameliorate a symptom of the dysautonomic disorder.

49. The method of claim 47 wherein the stool sample is measured using a technique selected from the group consisting of: enzymatic photospectrometry, colorimetry, treatment with substrates, assays, and a combination thereof.

Description

DETAILED DESCRIPTION

[0049] The present disclosure provides pharmaceutical compositions and methods for treating symptoms associated with CRPS, Pervasive Development Disorders, and Dysautonomias. The pharmaceutical compositions described herein include one or more digestive enzymes, which are postulated by the present inventor to assist in proper digest protein and thus to ameliorate the gastrointestinal dysfunction that is associated with the described disorders.

[0050] In certain embodiments, the pharmaceutical compositions can include one or more digestive enzymes, wherein the one or more digestive enzymes comprise at least one lipase and at least one protease, and wherein the ratio of total proteases to total lipases (in USP units) ranges from about 1:1 to about 20:1. In some cases, the ratio of total proteases to total lipases ranges from about 4:1 to about 10:1.

[0051] In some cases, a pharmaceutical composition for use herein comprises at least one amylase, at least one protease, and at least one lipase. In certain embodiments, the pharmaceutical composition includes multiple proteases, including, without limitation, chymotrypsin and trypsin. In certain embodiments, the composition can further include one or more hydrolases, papain, bromelain, papaya, celluloses, pancreatin, sucrases, and maltases.

[0052] The one or more enzymes can be independently derived from animal, plant, microbial, or synthetic sources. In some embodiments, the one or more enzymes are derived from pig, e.g.: pig pancreas.

[0053] One exemplary formulation for the treatment of the symptoms of complex regional pain syndrome is as follows:

[0054] Amylase 10,000-60,000 U.S.P

[0055] Protease 10,000-70,000 U.S.P

[0056] Lipase 4,000-30,000 U.S.P

[0057] Chymotrypsin 2-5 mg

[0058] Trypsin 60-100 mg

[0059] Papain 3,000-10,000 USP units/mg

[0060] Papaya 30-60 mg

[0061] Additional formulations comprising one or more digestive enzymes may be advantageous including formulations in which the ratio of total proteases to total lipases (in USP units) is from about 1:1 to about 20:1. In some embodiments, the ratio of total proteases to total lipases is from about 4:1 to about 10:1. Such formulations are useful for treating symptoms of CRPS as well as dysautonomias (e.g., familial dysautonomia, Parkinson's, Guillaine-Barre Syndrome, Aromatic-L-amino acid decarboxylase deficiency, tetrahydrobiopterin deficiency, familial paranganglioma syndrome; multiple system atrophy, dysautonomic symptoms associated with tumors such as pheochromocytoma, chemodectoma, and neuroblastoma; neurally mediated syncope, and SIDS) and pervasive development disorders such as autism, ADHD, ADD, and Asperger's.

[0062] Patients below the age of 18 are typically given a dosage such that the formulation would deliver at least 5,000 USP units of protease and no more than 10,000 USP units of lipase per kilogram weight of patient, per day. Beneficially the formulation would deliver at least 5,000 USP units of protease and no more than 7,500 USP units of lipase per kilogram weight of patient per day. Patients above the age of 18 are typically given no less than 5,000 USP units of protease per kilogram weight of patient per day.

[0063] The dosage formulation may be administered by an oral preparation including, but not limited to, an encapsulated tablet, mini-tabs, microcapsule, mini-capsule, time released capsule, sprinkle or other methodology. In one embodiment, the oral preparation is encapsulated using lipid. Alternatively, the oral preparation may be encapsulated using enteric coating or organic polymers. A formulation may also be prepared using Prosolv technology, direct compression, dry granulation, wet granulation, and/or a combination of these methods.

[0064] Fecal chymotrypsin level is a sensitive, specific measure of proteolytic activity, see e.g.: U.S. Pat. No. 6,660,831, incorporated by reference herein. Normal levels of chymotrypsin are considered be greater than 8.4 U/gram. Decreased values (less than 4.2 U/gram) suggest diminished pancreatic output (pancreatic insufficiency), hypoacidity of the stomach or cystic fibrosis. Elevated chymotrypsin values suggest rapid transit time, or less likely, a large output of chymotrypsin from the pancreas.

[0065] For the fecal chymotrypsin test, a stool sample is collected from each of the subjects. Each stool sample can be analyzed using an enzymatic photo spectrometry analysis to determine the level of fecal chymotrypsin in the stool; in some cases the assay is performed at 30 C., see e.g.: U.S. Pat. No. 6,660,831, incorporated by reference herein. Alternatively, other methods, such as the colorimetric method, use of substrates, use of assays, and/or any other suitable method may be used to measure the fecal chymotrypsin levels. The levels of fecal chymotrypsin in the samples of the individuals having complex regional pain syndrome are compared to the levels of fecal chymotrypsin in individuals not diagnosed with complex regional pain syndrome to determine if the individuals having complex regional pain syndrome would benefit from the administration of digestive enzymes.

[0066] The foregoing description of the embodiments of the disclosure has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. Many modifications and variations are possible in light of this disclosure. It is intended that the scope of the disclosure be limited not by this detailed description, but rather by the claims appended hereto.