Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-08-26
2002-04-16
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S062000, C514S054000, C514S012200, C514S801000, C530S362000
Reexamination Certificate
active
06372794
ABSTRACT:
FIELD OF THE INVENTION
The major constituents of cartilage are collagen and a variety of anionic high molecular weight carbohydrates (sulfated polysaccharides) associate with proteins in the form of proteoglycans. Both cartilage collagen and the cartilage specific carbohydrate moieties, more specifically the chondroitin sulfatate components of these carbohydrate fractions, are used with various degrees of success in treating patients afflicted with arthritis. The method of the present invention generates a mixture of these native molecules in concentrations and quality which reflect their proportions found in the native tissue. Ionic interactions between the collagen, which retains a fibrillar configuration, and the negatively charged sugars stabilizes the composition in the acid environment of the stomach and facilitates its dissociation in the alkaline environment of the small intestine. This has been found to be extremely effective in ameliorating symptoms and reversing changes associated with joint diseases in afflicted dogs and cats and appears to be equally effective in humans.
BACKGROUND OF THE INVENTION
Arthritis, particularly rheumatoid arthritis (RA), is a chronic, inflammatory disorder of unknown etiology, affecting approximately 1% of the world's population. Women are affected three to four times more often than men. Some populations are less affected (Asians and Nigerians), and others, such as certain Native American Indians, show a much higher incidence (5-6%).
In most patients symptoms begin as gradually increasing malaise and fatigue, likely to be accompanied by diffuse musculoskeletal pain. Joint involvement is appreciated as pain, tenderness, swelling, and redness. Symmetry is characteristic, most commonly involving the joints of the hands, wrists, elbows, and shoulders, but also involving the knees, ankles, and feet; virtually any diarthrodial joint can be affected.
Arthritis is associated with a decreased life span, in part because of the systemic nature of the disease and in part related to the toxicities of various treatments. The median life expectancy of persons with established arthritis is less than that of control populations. One study showed that median life expectancy was shortened by 7 years in males and 3 years in females.
Most patients exhibit a chronic fluctuating course of disease that, if left untreated, results in progressive joint destruction, deformity, disability, and premature death. RA results in more than 9 million physician visits and more than 250,000 hospitalizations per year in the USA. It frequently affects patients in their most productive years, and thus, disability results in major economic loss. There is no known cure for RA or means of preventing it. Optimal management requires early diagnosis and timely introduction of agents that reduce the probability of irreversible joint damage.
The initial drug treatment of RA usually involves the use of NSAIDs to reduce joint pain and swelling and improve function. If non-prescription drugs fail to help the patients, other drugs that require more careful monitoring are often used. All drugs used to treat RA may cause death, disability, and diseases, especially if the treatment continues in the setting of undetected toxicity. The incidence of toxicity may be reduced by pretreatment assessment of individual risk factors for toxicity and by careful patient and physician education about safe use of the drug. Patients must be alert to the sign and symptoms of toxicity that should prompt discontinuation of the drug and physician reassessment. Some drug toxicity may be discovered by appropriate laboratory monitoring before serious problems become clinically apparent.
In view of the hazards associated with the treatment of this disease, it is reasonable to expect that alternate, less potentially damaging approaches have been sought. Evidence suggests that dietary fish oil supplements may help alleviate symptoms of rheumatoid arthritis. The oil, obtained from cold-water fish, contains omega-3 polyunsaturated acids. Fish oil is known to prolong bleeding time and to inhibit platelet aggregation. These effects could be dangerous in patients taking other anticoagulants, including aspirin.
In 1993, a group of researchers in Boston (Trentham et al.) reported that a collagen preparation taken by mouth reduced inflammation in a small group of people with severe rheumatoid arthritis. These researchers used Type II collagen, a major component in joint cartilage. Animal studies by these and other investigators using a variety of animal models predicted these findings and preceded these studies in humans for many years.
Collagen is a protein that is a major component of all structural tissue in the body, including skin, bone, and joints. Type II collagen is the specific type of collagen found in cartilage and was first characterized in mammals by Strawich & Nhnni in 1971. Researchers believe that in rheumatoid arthritis, Type II collagen taken by mouth may turn off cells that are involved in causing inflammation or may prevent the immune system into responding to the inflammation.
Cartilage derived collagen (Type II) obtained from the breastbone extension of healthy chickens, is consumed in billions of households, yet cooking by denaturing the proteins, may inactivate the active substance. It still remains to be learned whether chicken soup, famous for its “therapeutic properties” may contain some biologically active derivatives. Even if this were the case, it would be difficult to standardize its activity and provide on a regular basis, pre-established amounts of active collagen by this route, which is essential for inducing immune tolerance orally to an antigenic substance.
Another cartilage containing substance, very different from collagen and the protein core of proteoglycans, and which is not a protein, includes a series of sulfated polysaccharides of which the chondroitin sulfate is amongst the best known species. These sulfated sugars have also been proposed to treat a variety of joint problems, particularly a non-inflammatory age related syndrome known as osteoarthritis or degenerative joint disease (DJD). Although distinct in nature rheumatoid arthritis and DJD usually have sufficient commonality to respond to similar treatment.
SUMMARY OF THE INVENTION
We have found that to alleviate arthritis it is important to orally administer native Type II collagen in helical form from mammalian cartilage ionically bound with sulfated polysaccharides. It is preferred if the weight ratio of the collagen to the polysaccharide is approximately the same as found in cartilage(i.e. about 6 to 1). The weight ratio may vary from about 5:1 to 30:1 with the preferred range being about 5:1 to 20:1. This approach yields a proper balance of the protein and carbohydrate components which are used to yield the building blocks for new material by the cartilage cells (particularly the sulfate moiety) and at the same time provide Type II collagen which decreases the severity of the inflammatory response.
As noted above, in my invention it is important to have the Type II collagen in helical form and ionically bound to the sulfated polysaccharides. This makes the composition of my invention very difficult to degrade by the enzymes in the gastrointestinal track. This allows my pharmaceutical compositions to have a slow “timed release” which is presently believed to, at least in part, account for the surprising results achieved in alleviating arthritis. It is also believed that having the Type II collagen in a fibrillar form is of benefit to achieve the slow “time release”.
It is generally preferred that the sulfated polysaccharides include chondroitin sulfate and even more preferred if more than 50%, by weight, (e.g. more than 75% by weight) of the polysaccharides be chondroitin sulfate. It is also preferred if the sulfated polysaccharides include keratan sulfate, as e.g. 5% or more by weight (up to about 10%). Thus, preferably, the total amount of sulfated keratan in my invention will be between about 2.5% by weight and
Criares Theodore J.
Farber Michael B.
Oppenheimer Wolff & Donnelly LLP
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