JP2002542205A - Treatment of adult rheumatoid arthritis by oral administration of stored human immunoglobulins and antacids - Google Patents

Abstract

  (57) [Summary] Stored human immunoglobulins and antacids can be administered orally to adult rheumatoid arthritis patients to treat the rheumatoid arthritis condition of those patients. Oral administration of stored human immunoglobulin together with antacids significantly improves the clinical level of disease activity in adult patients with rheumatoid arthritis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] Field of the Invention The present invention relates to the treatment of adult rheumatoid arthritis. More particularly, the present invention relates to the treatment of adult rheumatoid arthritis by oral administration of a pharmaceutical composition comprising stored human immunoglobulin together with an antacid.

BACKGROUND OF THE INVENTION adult rheumatoid arthritis is, in general, joint, particularly affecting the hands and feet of the joint, is a systemic inflammatory disease. The onset of rheumatoid arthritis can occur slowly, ranging from weeks to months, or the condition can appear acutely and rapidly.

[0003] Today, more than 2,500,00 individuals are diagnosed with adult rheumatoid arthritis in the United States alone (1% of the population), and some statistics indicate that between 65 and 8 million adults are affected. It indicates that the disease is potentially affected. Women are affected two to three times more often than men. Adult rheumatoid arthritis can also occur in young adults, and the incidence typically increases with age.

[0004] The classic early symptoms of adult rheumatoid arthritis include stiffness, tenderness, fever, subcutaneous nodules, acidic joints, and fatigue. The joints of the hands, feet, knees and wrists are the most affected, eventually involving the hips, elbows and shoulders. As the joints become hardened and swollen, any type of exercise becomes very painful and difficult. More severe cases of adult rheumatoid arthritis can lead to severe pain and eventual joint destruction. Approximately 300,000 bone and joint replacement surgical procedures are performed annually in an effort to ameliorate pain and loss of mobility resulting from joint destruction associated with arthritis.

[0005] Adult rheumatoid arthritis and juvenile rheumatoid arthritis are two different diseases. Juvenile rheumatoid arthritis is most common in children and includes eight different forms of the disease. One form of juvenile rheumatoid arthritis, Rf-positive polyarticular juvenile rheumatoid arthritis, is somewhat similar to adult rheumatoid arthritis. However, only about 40% of all juvenile rheumatoid arthritis is polyarticular, of course,
Only about 5 to 10% are rheumatoid factor (Rf) positive. Therefore, only 2 to 4% of patients with juvenile rheumatoid arthritis suffer from Rf-positive polyarticular juvenile rheumatoid arthritis.

[0006] 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 autoantibodies containing certain characteristic rheumatoid factors. The immunogenetic-related, clinical course, and functional consequences of juvenile rheumatoid arthritis are quite different from adult-onset rheumatoid arthritis. Rheumatic Diseases in Children: An Introduction to Rheumatic Diseases , 11th Edition, 1
997 (incorporated herein by reference).

[0007] Effective treatment of adult rheumatoid arthritis generally uses a combination of medication, exercise, rest and appropriate joint protection therapy. The therapy for a particular patient will depend on the disease involved and the severity of the joint. Aspirin is widely used for pain and for reducing inflammation. In addition to aspirin, nonsteroidal anti-inflammatory drugs, corticosteroids, gold salts, antimalarials and systemic immunosuppressants are widely used in moderate to advanced cases. However, the use of steroids and immunosuppressants has significant risks and side effects, both in terms of toxicity and vulnerability to potentially lethal conditions such as infections and malignancies. Accordingly, there is a need for a method of treating adult rheumatoid arthritis that does not include the potentially fatal side effects associated with the above treatments.

“Superantigens” are considered as stimulators of the immune system for various autoimmune diseases, including rheumatoid arthritis. Herman, A et al. (1991) Annu. Rev .. Immunol. 9: 745-772; Drake, C.I. G. FIG. And Kotz
in, B .; L. (1992) J. Clin. Immunol. 12: 149-162 (incorporated herein by reference). The gastrointestinal tract may be the site of immunostimulation with superantigens. Adult rheumatoid arthritis patients can be defective in their ability to produce antibodies with the correct neutralizing specificity. One approach to treating rheumatoid arthritis is to orally administer cow milk. U.S. Pat. No. 4,732,
No. 757 (Stolle et al.). Stole et al. Find that hyperimmune milk containing high titers of specific antibodies from animals, actively and artificially immunized and boosted with large amounts of purified antigen, is useful for the treatment of rheumatoid arthritis Is disclosed. The disadvantages to this approach are several-fold. The cow donor pool must be specifically and actively immunized against a small subset of antigens. further,
Several patients have side effects on consumption of bovine milk. In addition, cow milk does not contain the entire spectrum of antibodies present in humans. In addition, the effects of hyperimmune milk on inflammatory processes such as rheumatoid arthritis have largely been discarded. Or
mrod and Miller (1991) Agents and Action s , 32 (3/4): 160 166 referenced.

[0009] Another approach to the treatment of autoimmune diseases, one example of which is rheumatoid arthritis, is the tolerization of patients with the autoimmune disease to the specific autoantigen (s) involved in the disease. Weiner et al., Science 259: 1321-132.
4 (1993) (incorporated by reference herein), patients with multiple sclerosis
Bovine myelin protein containing two multiple sclerosis autoantigens was administered orally. Tr
Entam et al., Science 261: 1727-1730 (1993).
In (incorporated by reference herein), a patient with rheumatoid arthritis was orally administered collagen, a putative autoantigen. One drawback to tolerization is the identification of the correct self-antigen to induce tolerance.

[0010] In view of the unsuccessful and disadvantageous aspects currently used, there remains a need for the development of methods and compositions that are effective in treating adult autoimmune rheumatoid arthritis.

[0011] SUMMARY OF THE INVENTION The present invention is an adult due to with antacid is orally administered a sufficient amount of storage human immunoglobulin providing clinically observable improvement in the patient with rheumatoid arthritis condition The present invention relates to a method for treating rheumatoid arthritis patients. The present invention is based on the finding that oral administration of stored human immunoglobulin together with antacids to adult rheumatoid arthritis patients results in a significant clinical improvement in the rheumatoid arthritis condition of the patients. The present invention is also based on the discovery that oral administration of stored human immunoglobulin together with antacids to adult rheumatoid arthritis patients has no toxic effects.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method of treating a patient with adult rheumatoid arthritis. This is achieved by orally administering a stored human immunoglobulin together with an antacid. Immunoglobulins introduced into the acidic environment of the human stomach can undergo inactivation. To alleviate such inactivation and / or provide increased therapeutic efficacy, the stored human immunoglobulins used in the methods of the invention are administered with an antacid. The present invention also relates to a pharmaceutical composition comprising stored human immunoglobulin and an antacid. Although not wishing to consolidate a particular mechanism, acid blockers may neutralize another acidic feature of the intestine, thereby blocking the digestion of immunoglobulins in the stomach. Alternatively, acid blockers and immunoglobulins may synergistically provide treatment for arthritic conditions by suppressing inflammatory mediators or immune-mediated inflammation.

Surprisingly, according to the present invention, encapsulated immunoglobulin IgG aimed at avoiding the acidic characteristics of the stomach and providing a sustained release in the intestine is now more remarkable compared to uncoated IgG It was found to show no improvement. This determination demonstrates that the antacids act not only to block immunoglobulins from the gut, but also to act synergistically to enhance the efficacy of the immunoglobulins. Thus, the present invention provides increased potency compared to stored human immunoglobulins administered alone,
A pharmaceutical composition comprising a stored immunoglobulin and an antacid is contemplated.

The term “storage human immunoglobulin” as used herein refers to an immunoglobulin composition comprising polyclonal antibodies obtained from the plasma of thousands of human donors. Polyclonal antibodies can include IgG, IgA, IgM, etc. or fragments thereof. A preferred polyclonal antibody is IgG. Preferred immunoglobulin compositions include at least about 90% IgG polyclonal antibodies and trace amounts of other polyclonal antibodies, such as IgA and IgM. Examples of storage human immunoglobulin compositions useful according to the present invention include, but are not limited to, Sandglobulin®, Gammaguard®, Gamimune®, and Gamma®. According to the present invention, any stored human immunoglobulin can be used.

[0015] were used herein, "antacids" reduces the acid content of the intestinal neutralization and / or significantly, indicating with H ₂ blocker or an acid blocker or other acid neutralizing agent. A preferred antacid useful according to the technique of the present invention is cimetidine.

As used herein, “clinically observable improvement” refers to a patient's rheumatoid arthritis condition, including but not limited to tender joint (s), swollen joint (s), and sclerosis assessment. It means the cure of the associated significant subjective symptoms. Significant subjective healing of symptoms indicates the patient's self-assessment or physician assessment of sclerosis, joint tenderness, swelling, etc. For example, observable differences in swelling or tenderness in only one rheumatoid joint are also important. Most importantly, the affected joints are not swollen or tender.

Another aspect of the present invention provides a pharmaceutical composition comprising a stored human immunoglobulin, an antacid and a pharmaceutically acceptable carrier. In a preferred embodiment, the composition comprises
Includes Sandglobulin®, Cimetidine and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” as used herein 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 in pharmaceutically active substances is known in the art. As long as any conventional vehicle or substance is compatible with the active ingredient, its use in therapeutic compositions is contemplated.

“Treatment” as used herein includes indices for ameliorating, suppressing, alleviating or eliminating the clinical symptoms following the onset (ie, clinical signs) of adult rheumatoid arthritis.

“Oral” administration as used herein includes oral, enteral or gastric administration.

“With” as used herein means before, substantially simultaneously with, or after oral administration of the antacid. Of course, the immunoglobulin composition cannot be before or after the antacid by the time when the relevant effect of the administered substance first ends. Therefore, the immunoglobulin composition is usually administered within a therapeutically effective time. By "therapeutically effective time" as used herein is meant a time frame in which the antacid or immunoglobulin is still active in the patient.

In a preferred embodiment, the stored human immunoglobulin is produced by cold alcohol (eg, ethanol) fractionation from the plasma of thousands of human volunteer subjects.

In another preferred embodiment, the stored human immunoglobulin is purchased from Novartis Pharmaceuticals, which is sold under the name Immunoglobulin Intravenous (Human) Sandglobulin®. Sandglobulin® is a sterile, highly purified, multivalent antibody product that contains all IgG antibodies that occur regularly in the donor population in concentrated form. This immunoglobulin preparation contains 16,
Produced from the cold alcohol fraction from the plasma of more than 000 volunteers.
Sandglobulin® (IGIV) is suitable for intravenous use by treatment at acidic pH in the presence of trace amounts of pepsin. The preparation contains at least 96% of I
The neutralizing unbuffered diluent containing gG has a pH of 6.6 ± 0.2. Most immunoglobulins are monomeric (7S) IgG; the rest consists of dimeric and minor amounts of multimeric IgG, minor amounts of IgA and IgM and immunoglobulin fragments [
Roemer, J, Spaeth PJ: Molecular composition of immunoglobulin preparations and their relation to complement activation, Nydegger UE (eds.): Immunochemotherapy : Guide to immunoglobulin prevention and treatment , London, Academic Press,
1981, 123]. The distribution of the IgG subclass corresponds to the distribution of normal serum. The final container lyophilization unit is prepared to contain 1, 3 or 6 g of protein with 1.67 g of sucrose and up to 20 mg of NaCl per g of protein. Lyophilized preparations contain no preservatives and can be reconstituted with sterile water.

In yet another preferred embodiment, the stored human immunoglobulin is purchased from Baxter Healthcare Corporation, which is sold under the name Immunoglobulin Intravenous (Human) GammaGuard®. GammaGuard® is a highly purified immunoglobulin G obtained from a large pool of human plasma.
1 is a sterile lyophilized preparation of (IgG). Gammaguard® is manufactured by cold ethanol fractionation. Gamma Guard® has at least about 90
% IgG and trace amounts of IgA and IgM. GammaGard®, reconstituted to 5%, contains physiological concentrations of sodium chloride (about 8.5 mg / mL
) And has a pH of 6.8 ± 0.4. The distribution of the IgG subclass is similar to that of normal plasma. Gammaguard® is 2.5, 5 or 10 g of 1
It is freeze-dried and supplied to a single-use bottle. The GammaGard® in each bottle is provided with an appropriate volume of sterile water for reconstitution.

[0024] In yet another preferred embodiment, the stored human immunoglobulin is purchased from Bayer Corporation, which is sold under the name Gamimune®. Gamimune® is a sterile solution of highly purified human protein. Gamimun® contains 9-11% protein in 0.16-0.24M glycine. At least about 90% of the protein is IgG
It is a monomer. Gamimun® also contains trace amounts of IgA and IgM. The distribution of the IgG subclass is similar to that found in normal human serum. Gamimun® and Sandglobulin®, such as Gammaguard®, are made by cold ethanol fractionation of a pool of human plasma obtained from thousands of volunteers.

In yet another preferred embodiment, the stored human immunoglobulin is Centenon, L. et al. L. C. And it is sold under the name of immunoglobulin intravenous (human) gamma®. Gamma® is 16.5 ± 1
A sterile solution of immunoglobulins, mainly immunoglobulin G (IgG), containing 5% protein. Gamma® is prepared by cold alcohol fractionation of stored plasma from at least 1000 donors. The pH of Gamma® is 6.8 ± 0.4. Gamma® also contains about 0.45% sodium chloride, 0.01% concentration thimerosal and 0.3 M glycine. The above stored human immunoglobulin preparations are merely an example of a class of stored human immunoglobulin preparations useful according to the present invention.

An antacid is administered with the stored immunoglobulin to enhance the efficacy of the introduced immunoglobulin in the treated patient and provide a clinically observable improvement. In a preferred embodiment, the immunoglobulin composition and the antacid are administered simultaneously in a unit pharmaceutical composition. In another preferred embodiment, the immunoglobulin composition is administered at a therapeutically effective time after administration of the antacid. Preferably, the antacid is aluminum or magnesium hydroxide, such as Marlox®, Miranta® or Tagamet®, which is commercially available. Most preferably, the antacid is an H2 blocker, such as cimetidine or ranitidine.

The dose of antacid administered together with immunoglobulin is dependent on the specific H ₂ blockers used. 15 ml to 3 ml when the antacid is Miranta (registered trademark)
0 ml is preferred. Most preferably, the dose of Miranta® is 15 ml. If a cimetidine H2 blocker is used, the preferred dose is 4 per day.
00 to 800 mg.

[0028] The dose of stored human immunoglobulin to be administered to a patient can vary depending on the severity of the patient's arthritis condition and other clinical factors. Preferably, the dose is as small as possible while still providing clinically observable results. The most preferred dose is that having the greatest effect in reducing the patient's arthritis condition. The dosage of the immunoglobulin composition can range from as little as 100 mg to as much as 10 g per day. A dose of 1000 mg of stored human immunoglobulin per day has been found to provide significant improvement in the condition of rheumatoid arthritis patients with little or no side effects. Therefore, 1000 mg per day is a preferred dose.

The selected dose may be given in escalating amounts, but it may also be given as a single dose. In addition, the dose of immunoglobulin may be administered at any time of the day, but is preferably administered in the morning prior to substantial patient activity.

The arthritic condition of a patient can be determined, for example, by the patient's self-assessment or his or her pain, stiffness, and the like. Another way to determine a patient's arthritis condition is for a physician to examine the patient for joint tenderness and swelling.

It is especially advantageous to formulate stored human immunoglobulins in unit dosage form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable as unit dosages for the rheumatoid arthritis subject to be treated, each unit with the desired pharmaceutical carrier together with the required pharmaceutical carrier. Contains a predetermined amount of stored human immunoglobulin in the presence or absence of an antacid, calculated to produce a therapeutic effect. The specifications of the novel dosage units of the present invention include (a) the unique characteristics of stored human immunoglobulins, antacids and the specific therapeutic effect one wishes to achieve, and (b) adult rheumatoid It is indicated and directly dependent on the limitations inherent in the field of formulating stored human immunoglobulins for the treatment of arthritis.

[0032] The stored human immunoglobulin in the presence or absence of an antacid is formulated for convenient and effective administration of an effective amount in a dosage unit form as described herein above. For example, dosage unit forms may contain stored human immunoglobulins in amounts ranging from about 100 mg to about 10 g, and, if desired, antacids in amounts ranging from about 400 mg to 800 mg.

[0033] Clinically observable results from administration of antacids and immunoglobulins can be observed in as little as two weeks. However, it can take six weeks to get measurable benefits. The initial dose level used during the first few weeks of treatment may be reduced once clinical improvement is observed. Dose level reductions of up to 90% can be made after the first few weeks.

The oral treatment methods according to the present invention may be used to treat adult rheumatoid arthritis and spondyloarthritis, including but not limited to ankylosing spondylitis (AS), psoriatic arthritis, Reiter's syndrome, and ulcerative colitis And other closely related autoimmune diseases such as arthritis of inflammatory bowel disease, including but not limited to Crohn's disease. The treatment of spondyloarthritis according to the present invention uses the same dose and the same treatment protocol as rheumatoid arthritis.

A demonstration of treatment of a patient according to the present invention is shown in the following non-limiting examples.

Example 1 An open label test was performed to evaluate the safety of oral gamma globulin. Five patients with severe non-remissioning rheumatoid arthritis unresponsive to conventional therapy were selected. The patient continued to receive the prescribed medical treatment and for an additional 6 weeks
A single dose of 1 g of encapsulated (uncoated) gamma globulin was administered. There was no evidence of toxicity as a result of receiving oral gamma globulin. In addition, three out of five patients showed an improvement in tenderness and number of swollen joints.

Based on the Phase I study, a Phase II FDA-approved, double-blind, placebo-controlled study was conducted to determine the efficacy of oral gamma globulin in rheumatoid arthritis in patients with severe non-responsive rheumatoid arthritis. Performed on one patient. 8 patients 1g daily for 2 months
Of non-coated gamma globulin, 10 patients received 1 g of enteric coated gamma globulin daily for 2 months, and 10 patients received standard drug-containing anti-rheumatic drugs (DMARDs). Taking optimal therapy with various substances. Oral gamma globulin was discontinued after two months, but the patient was followed for disease activity for an additional two months.

At 3 months of observation, 50% (4%) of patients treated with uncoated gamma globulin
/ 8) met the ACR criteria with a 20% improvement compared to 11% in the placebo group (1/9) (p <0.05).

[0039] All groups of 18 patients treated with gamma globulin showed a significant decrease in the number of swollen joints. Improvement was observed at every follow-up visit compared to the first visit and was reduced by about 40% overall at 3 and 4 months (p <0.01). In contrast, the placebo group
There was no significant reduction in swollen joints at any time during the course of the study compared to the initial examination. In addition, 5 patients with significantly reduced joint swelling treated with gamma globulin
Humans have shown at least a 4-fold decrease in serum levels of C-reactive protein, rheumatoid factor, or both over the course of the study.

[0040] 400 mg / day each test of patients taking of H ₂ blocker cimetidine was best respond to oral γ-globulin. There are no side effects attributable to taking oral gamma globulin in this study. The results of this test, the oral administration of H ₂ blockers and γ-globulin has been shown to be effective in the treatment of rheumatoid arthritis. The lack of toxicity has been shown to make this treatment highly advantageous over other treatments or in combination with other treatments for rheumatoid arthritis.

The following is a description of patients taking both H ₂ blockers and oral immunoglobulin. These patients had the best clinical response. The patient improved by over 80%. In particular, the patient improved on tender and swollen joints and the physician's comprehensive evaluation.

Patient No. 127, (CEG) A 75 year old white male with a history of 14 years of seropositive rheumatoid arthritis. He was one patient in a placebo-controlled, double-blind study taking oral gamma globulin in combination with cimetidine (400 mg / day). Patient was receiving a stable dose of cimetidine at the start of the study. This patient had a clinically observable response. At the first visit, he had 18 tenderness and 17 swollen joints. At the fourth visit, he had only three tender and swollen joints,
Or had an 82% improvement. The physician's initial comprehensive assessment was 8.0. At the fourth visit, the global assessment was 4.0 (Table I).

[0043]

[Table 1] Patient # 5 (RR) A 70 year old male with a 12 year history of seropositive rheumatoid arthritis with rheumatoid nodules. RR had a severe uncontrolled disease involving almost exclusively the hands and wrists, with erosion, deformation and stiffness lasting all day. RR had previously received gold therapy but was discontinued due to toxicity. RR was methotrexate at 15 mg / week,
Sulfasalazine 1 mg / day, Indosine® 25 mg at bedtime, Motrin® 1600 mg / day, Praquenil® 400 mg / day,
And Tagamet® 400 mg / day. Patient RR responded to oral immunoglobulin (administered 3 weeks later) with clinically observable improvement, but developed redness two weeks after discontinuing oral immunoglobulin (Table II).

[Table 2]

[Brief description of the drawings]

FIG. 1 is a graph of joint tenderness and swelling of a patient GEC treated with oral gamma globulin in combination with cimetidine.

FIG. 2 is a graph of joint tenderness and swelling of patient RR treated with oral gamma globulin in combination with cimetidine.

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Claims (17)

[Claims] 1. A method of treating adult autoimmune rheumatoid arthritis in a patient, the method comprising administering to the patient, together with an antacid, a clinically observable improvement in the patient's rheumatoid arthritis. Such a method, comprising orally administering an immunoglobulin composition comprising an amount of stored human immunoglobulin. 2. The method of claim 1, wherein said immunoglobulin comprises a stored human polyclonal IgG antibody. 3. The method according to claim 2, wherein the immunoglobulin composition is selected from the group consisting of Sandglobulin®, Gammaguard® or Gamimune®. 4. The method according to claim 1, wherein the antacid is aluminum hydroxide, magnesium hydroxide,
2. The method of claim 1, wherein the method is selected from the group consisting of cimetidine or ranitidine. 5. The method according to claim 1, wherein the amount of the immunoglobulin administered to the patient is 2 per day.
The method of claim 1, wherein the amount is between 50 mg and 10 g. 6. The method of claim 5, wherein the amount of the immunoglobulin composition administered to the patient is about 1000 mg per day. 7. The amount of antacid administered to the patient is 200 mg per day.
The method of claim 1, wherein the weight is between about 800 mg. 8. The amount of antacid administered to the patient is about 400 m / day.
The method of claim 7, wherein g is g. 9. The method of claim 1, wherein said immunoglobulin composition is administered in a unit dosage form. 10. The method of claim 1, wherein said antacid is administered in a unit dosage form. 11. The method of claim 1, wherein said immunoglobulin composition is in a powder form. 12. The method of claim 1, wherein said immunoglobulin composition is dispersed in a pharmaceutically acceptable carrier. 13. The method of claim 1, wherein said immunoglobulin composition and said antacid are administered to said patient simultaneously. 14. The method of claim 1, wherein said immunoglobulin composition is administered at a therapeutically effective time after administration of said antacid. 15. A pharmaceutical composition comprising a stored human immunoglobulin, an antacid and a pharmaceutically acceptable carrier. 16. The pharmaceutical composition according to claim 15, wherein said stored human immunoglobulin is Sandglobulin®. 17. The pharmaceutical composition according to claim 15, wherein said antacid is cimetidine.