Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the treatment of adult rheumatoid arthritis. More particularly, the invention relates to the treatment of adult rheumatoid arthritis by oral administration of a pharmaceutical composition comprising pooled human immunoglobulin in conjunction with an antacid.
• rheumatoid arthritis is a systematic inflammatory disease that commonly affects the joints, particularly those of the hands and feet. The onset of rheumatoid arthritis can occur slowly, ranging from a few weeks to a few months, or the condition can surface rapidly in an acute manner .
• the classic early symptoms of adult rheumatoid arthritis include stiffness, tenderness, fever, subcutaneous nodules, achy joints, and fatigue.
• the joints of the hands, feet, knees and wrists are most commonly affected, with eventual involvement of the hips, elbows and shoulders.
• any type of motion becomes very painful and difficult.
• the more severe cases of adult rheumatoid arthritis can lead to intense pain and eventual joint destruction.
• Some 300,000 bone and joint replacement surgical procedures are performed annually in an effort to alleviate the pain and mobility loss resultant from arthritis related joint destruction.
• Juvenile rheumatoid arthritis is characterized by abnormal T and B cell function and selective IgA deficiency.
• Adult rheumatoid arthritis is a disease identified by the presence of auto-antibodies including certain characteristic rheumatoid factors.
• the immunogenetic associations, clinical course, and functional outcome of juvenile rheumatoid arthritis are quite different from adult -onset rheumatoid arthritis.
• the effective treatment of adult rheumatoid arthritis has generally employed a combination of medication, exercise, rest and proper joint protection therapy.
• the therapy for a particular patient depends on the severity of the disease and the joints that are involved.
• Aspirin is widely used for pain and to reduce inflammation.
• non- steroidal anti- inflammatory drugs, corticosteroids , gold salts, anti-malarials and systemic immuno- suppressants are widely used in moderate to advanced cases.
• steroids and immunosuppressants however, has significant risks and side effects both in terms of toxicity and vulnerability to potentially lethal conditions such as infection and malignancy.
• Superantigens have been considered as stimulants of the immune system in various autoimmune diseases including rheumatoid arthritis.
• the gastrointestinal tract may be the site of immunologic stimulation by superantigens.
• One approach to treating rheumatoid arthritis is to orally administer cow's milk to patients. See U.S. Patent No.
• rheumatoid arthritis Another approach to the treatment of autoimmune diseases, of which rheumatoid arthritis is an example, is tolerization of the patient suffering from the autoimmune disease to the particular autoantigen (s) involved in the disease.
• autoantigen s
• multiple sclerosis patients were orally administered bovine myelin protein, which contains two multiple sclerosis autoantigens .
• rheumatoid arthritis patients were orally administered collagen, a presumed autoantigen.
• the present invention is directed to a method for treating an adult rheumatoid arthritis patient by orally administering an amount of pooled human immunoglobulin in conjunction with an antacid which is sufficient to provide a clinically observable improvement in a patient's rheumatoid arthritic condition.
• the present invention is based on the discovery that the oral administration of pooled human immunoglobulin in conjunction with antacids, to patients with adult rheumatoid arthritis results in a significant clinical improvement in the rheumatoid arthritic condition of the patient.
• the present invention is also based on the discovery that there are no toxic effects of orally administered pooled human immunoglobulin in conjunction with an antacid to adult rheumatoid arthritis patients.
• Fig. 1 is a Joint Tenderness and Swelling graph for patient GEC who was treated with oral gammaglobulin in combination with cimetidine.
• Fig. 2 is a Joint Tenderness and Swelling graph for patent RR who was treated with oral gammaglobulin in combination with cimetidine. DETAILED DESCRIPTION OF THE PRESENT INVENTION
• the present invention concerns a method for treating a patient with adult rheumatoid arthritis. This is accomplished by orally administering pooled human immunoglobulin in conjunction with an antacid.
• An immunoglobulin introduced into the acidic environment of the human stomach, may suffer inactivation.
• the pooled human immunoglobulin employed in the method of the present invention is administered in conjunction with an antacid.
• the present invention also contemplates pharmaceutical compositions comprising pooled human immunoglobulin and an antacid. While not wishing to be bound to a particular mechanism, the acid blocker may neutralize the otherwise acidic character of the gut thereby shielding the immunoglobulin from digestion in the stomach.
• the acid- blocker and immunoglobulin may synergistically provide remediation of arthritis symptoms by suppressing inflammatory mediators or immune-mediated inflammation.
• encapsulated immunoglobulin IgG intended to avoid the acidic character of the stomach and provide sustained release in the intestines, does not manifest any noticeable improvement relative to uncoated IgG.
• the antacid is not merely shielding the immunoglobulin from the gut, but acting synergistically to improve the effectiveness of the immunoglobulin.
• the present invention contemplates pharmaceutical compositions containing pooled immunoglobulin and an antacid which provides increased efficacy relative to pooled human immunoglobulin administered alone.
• pooled human immunoglobulin refers to an immunoglobulin composition containing polyclonal antibodies obtained from the plasma of thousands of human donors.
• the polyclonal antibodies may include IgG, IgA, IgM, etc. or fragments thereof.
• a preferred polyclonal antibody is IgG.
• a preferred immunoglobulin composition contains at least about 90% IgG polyclonal antibodies and trace amounts of other polyclonal antibodies such as, for example, IgA and IgM.
• Examples of pooled human immunoglobulin compositions useful in accordance with the present invention include, but are not limited to, Sandoglobulin®, Gammagard®,
• Gamimune® and Gammar® In accordance with the present invention any pooled human immunoglobulin can be used.
• a preferred antacid when used herein denotes an H 2 - blocker or acid blocker or other acid neutralizing agent which neutralizes and/or significantly reduces the acidic content of the gut.
• a preferred antacid useful in accordance with the teachings of the present invention is cimetidine.
• a "clinically observable improvement" when used herein refers to a significant subjective remediation of symptoms associated with the patient's rheumatoid arthritic condition including, but not limited to, tender joint(s), swollen joint(s) and stiffness assessments.
• Significant subjective remediation of symptoms denotes a patient's self -assessment or a physician's assessment of stiffness, joint tenderness, swelling and the like. For example, an observable difference in swelling or tenderness in even one arthritic joint is significant. Absence of swelling or tenderness in a previously affected joint is most significant.
• compositions comprising pooled human immunoglobulin, an antacid and a pharmaceutically acceptable carrier.
• the composition comprises Sandoglobulin®, cimetidine and a pharmaceutically acceptable carrier.
• pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients, its use in the therapeutic compositions is contemplated.
• Treating as used herein includes measures to ameliorate, suppress, mitigate or eliminate the clinical symptoms after the onset (i.e., clinical manifestation) of adult rheumatoid arthritis.
• Oral administration as used herein includes oral, enteral or intragastric administration.
• the immunoglobulin composition can not precede or follow administration of an antacid by so long an interval of time that the relevant effects of the substance administered first have expired. Therefore, the immunoglobulin composition should usually be administered within a therapeutically effective time.
• therapeutically effective time is meant a time frame in which the antacid or immunoglobulin is still active within the patient.
• the pooled human immunoglobulin is produced by cold alcohol (e.g., ethanol) fractionation from the plasma of thousands of human volunteers .
• pooled human immunoglobulin is purchased from Novartis Pharmaceuticals, where it is sold under the name Immune Globulin Intravenous (Human) Sandoglobulin®.
• Sandoglobulin® is a sterile, highly purified polyvalent antibody product containing, in concentrated form, all the IgG antibodies which regularly occur in the donor population. This immunoglobulin preparation is produced by cold alcohol fractionation from the plasma of over
• Sandoglobulin® (IGIV) is made suitable for intravenous use by treatment at acid pH in the presence of trace amounts of pepsin.
• the preparation contains at least 96% of IgG and with a neutral unbuffered diluent has a pH of 6.6 ⁇ 0.2.
• immunoglobulins are monomeric (7 S) IgG; the remainder consists of dimeric IgG and a small amount of polymeric IgG, traces of IgA and IgM and immunoglobulin fragments [R ⁇ mer J, Spath PJ: Molecular composition of immunoglobulin preparations and its relation to complement activation, in Nydegger UE (ed) : Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, p. 123.]. The distribution of the IgG subclasses corresponds to that of normal serum.
• Final container lyophilized units are prepared so as to contain 1, 3 or 6 g protein with 1.67 g sucrose and less than 20 mg NaCl per gram of protein.
• the lyophilized preparation is devoid of any preservatives and may be reconstituted with sterile water.
• pooled human immunoglobulin is purchased from the Baxter
• Gammagard® is a sterile, freeze dried preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma.
• IgG immunoglobulin G
• Gammagard® is manufactured by cold ethanol fractionation.
• Gammagard® contains at least about 90% IgG and trace amounts of IgA and IgM.
• Gammagard® reconstituted to 5%, contains a physiological concentration of sodium chloride (approx. 8.5 mg/mL) and has a pH of 6.8 ⁇ 0.4.
• the distribution of IgG subclasses is similar to that in normal plasma.
• Gammagard® is supplied lyophilized in 2.5, 5 or 10 g single use bottles. Each bottle of Gammagard® is furnished with a suitable volume of sterile water for reconstitution.
• pooled human immunoglobulin is purchased from the Bayer Corporation, where it is sold under the name Gamimune®.
• Gamimune® is a sterile solution of highly purified human protein.
• Gamimune® contains 9-11% protein in 0.16-0.24 M glycine. At least about 90% of the protein is IgG monomer
• Gamimune® also contains traces of IgA and IgM. The distribution of IgG subclasses is similar to that found in normal human serum.
• Gamimune® like Gammagard® and Sandoglobulin® is made by cold ethanol fractionation of pools of human plasma obtained from thousands of volunteers .
• pooled human immunoglobulin is purchase from Centeon, L.L.C., where it is sold under the name Immune Globulin Intravenous (Human) Gammar®.
• Gammar® is a sterile solution of immunoglobulin, primarily immunoglobulin G (IgG), containing 16.5 ⁇ 15% protein.
• Gammar® is prepared by cold alcohol fractionation of plasma pooled from at least 1000 donors. The pH of Gammar® is 6.8 ⁇ 0.4.
• Gammar® also contains approximately 0.45% sodium chloride, thi erosal, at a concentration of 0.01% and 0.3M glycine.
• an antacid is administered in conjunction with the pooled immunoglobulin.
• the immunoglobulin composition and the antacid are administered simultaneously in a unitary pharmaceutical composition.
• the immunoglobulin composition is administered at a therapeutically effective time after administration of the antacid.
• the antacid is aluminum hydroxide or magnesium hydroxide such as Maalox®, Mylanta® or Tagamet® which are available commercially.
• the antacid is an H2 blocker, such as Cimetidine or Ranitidine.
• the dosage of antacid administered in conjunction with immunoglobulin depends on the particular H 2 -blocker used.
• the antacid is Mylanta®, between 15 ml and 30 ml is preferred. Most preferably the dosage of Mylanta® is 15 ml.
• the cimetidine H2 blocker is used, the preferred dosage is between 400 and 800 mg per day.
• the dosage of pooled human immunoglobulin administered to the patient may be varied dependent upon severity of the patient's arthritic condition and other clinical factors. Preferably, the dosage will be as small as possible while still providing a clinically observable result.
• the most preferable doses are those that have the largest effect in terms of alleviating the patient's arthritic condition.
• Dosages of the immunoglobulin composition may range from as little as 100 mg per day up to as much as 10 g per day.
• Dosages of 1000 mg of pooled human immunoglobulin per day have been found to result in significant improvement in the condition of patients with rheumatoid arthritis and cause little or no adverse side effects. Accordingly, 1000 mg per day is a preferred dose.
• the chosen dose may be given in increments, it also may be given as a single dose.
• the dose of immunoglobulin may be administered at any time during the day, it is preferred that it be administered in the morning, prior to substantial patient activity.
• the patient's arthritic condition can be determined, for example, by the patient's self -assessment of his or her pain, stiffness, etc. Another way to determine the patient's arthritic condition is for a physician to examine a patient's joint tenderness and swelling. It is especially advantageous to formulate the pooled human immunoglobulin in dosage unit form for ease of administration and uniformity of dosage.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the rheumatoid arthritic subjects to be treated, each unit containing a predetermined quantity of pooled human immunoglobulin with or without an antacid calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the pooled human immunoglobulin, antacid and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a pooled human immunoglobulin for the treatment of adult rheumatoid arthritis herein disclosed in detail.
• the pooled human immunoglobulin with or without an antacid is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore described.
• a unit dosage form can, for example, contain the pooled human immunoglobulin in amounts ranging from about 100 mg to about 10 g and, if desired, an antacid in an amount ranging from about 400 to 800 mg.
• Clinically observable results from the administration of immunoglobulin in conjunction with antacid may be observed in as little as 2 weeks. However, it may take up to 6 weeks to obtain measurable benefit. Initial dose levels used during the first few weeks of treatment may be reduced once clinical improvement has been observed. Reductions in dose levels of up to 90% may be made after the first few weeks.
• the oral treatment method in accordance with the present invention may be used to treat adult rheumatoid arthritis and other closely related autoimmune diseases such as spondyloarthopathies including but not limited to Ankylosing Spondylitis (AS) , psoriatic arthritis, Reiter's Syndrome and the arthritis of inflammatory bowel disease including, but not limited to, ulcerative colitis and Crohn's disease.
• spondyloarthopathies including but not limited to Ankylosing Spondylitis (AS) , psoriatic arthritis, Reiter's Syndrome and the arthritis of inflammatory bowel disease including, but not limited to, ulcerative colitis and Crohn's disease.
• the treatment of spondyloarthopathies according to the present invention would employ the same dosages as for rheumatoid arthritis and the same treatment protocol .
• Phase II FDA approved double-blind placebo controlled trial was conducted in 28 patients with severe unresponsive rheumatoid arthritis to determine the efficacy of oral gammaglobulin in rheumatoid arthritis.
• Oral gammaglobulin was discontinued after 2 months, but the patients were followed for disease activity for an additional 2 months.
• the entire group of 18 patients treated with gammaglobulin showed a significant reduction in the number of swollen joints. The improvement was observed at every follow-up visit compared to the initial visit with an overall reduction of about 40% by the third and fourth months (p ⁇ 0.01). In contrast, the placebo group did not show a significant reduction of swollen joints at any time in the course of the study compared to the initial examination. Furthermore, 5 of the patients with markedly reduced joint swelling treated with gammaglobulin showed at least 4 -fold reductions in serum levels of C-reactive protein, rheumatoid factor, or both during the course of the study.
• RR a 70 year old male with 12 year history of sero-positive rheumatoid arthritis with rheumatoid nodules. RR had severe uncontrolled disease almost exclusively involving his hands and wrists with erosions, deformities, and stiffness lasting all day. RR previously received gold therapy, but it was discontinued because of toxicity. RR was receiving methotrexate 15 mg/week, sulfasalazine 1 gm/day, Indocin® 25 mg at bedtime, Motrin® 1600 mg/day, Plaquenil® 400 mg/day, and Tagamet® 400 mg/day. Patient RR responded to oral immunoglobulin (given post -week 3) with clinically observable improvement, but flared two weeks after oral immunoglobulin was discontinued. (Table II) .

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• 1999
  • 1999-04-19 JP JP2000611942A patent/JP2002542205A/ja active Pending
  • 1999-04-19 CA CA002370268A patent/CA2370268A1/en not_active Abandoned
  • 1999-04-19 EP EP99917625A patent/EP1171161A1/en not_active Withdrawn
  • 1999-04-19 WO PCT/US1999/008578 patent/WO2000062806A1/en not_active Application Discontinuation

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