Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-07-06
2003-03-25
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06537978
ABSTRACT:
This application is a U.S. National Phase Application of PCT/CA97/00007, filed on Jan. 8, 1997, which claims priority to Canadian Applications 2,167,044, filed on Jan. 11, 1996, and 2,193,921, filed on Dec. 24, 1996.
FIELD OF INVENTION
This invention relates to the oral administration of forms of hyaluronic acid (for example hyaluronan (hyaluronic acid) and pharmaceutically acceptable salts thereof such as sodium hyaluronate), and orally administrable dosage forms containing forms of hyaluronic acid, for the prevention and/or treatment of diseases and/or conditions such as the prevention of restenosis and the treatment of an infarct (heart attack) or a stroke. The oral administration and the orally administered dosage forms may also include therapeutic agents and/or medicines which may be administered orally for the treatment and/or prevention of the diseases and/or conditions with the forms of hyaluronic acid (hyaluronan).
BACKGROUND OF THE INVENTION
In International Publication W095/26193 (Application PCT/CA94/00188), hyaluronic acid and/or pharmaceutically acceptable salts thereof are administered to prevent restenosis of the arterial walls when the artery walls are traumatized by for example balloon angioplasty.
Generally a newborn's arteries each consist of the outer adventitia and inner intima. The inner surface of the intima presents an elastic lamina. As the newborn grows into an adult human, a neointima (made of migrating smooth muscle cells, leucocytes (macrophages) and fat deposited in the leucocytes (macrophages)(in foamy cells)), develops radially inwardly of the intima, thus narrowing or constricting the opening in the artery (stenosis). This narrowing or constriction reduces blood flow. The development of the neointima depends on the human's diet, physical conditioning and physical and genetic make-up.
In some people, the size of the neointima has substantially constricted the blood flow through the artery, jeopardizing the human's life. In an attempt to reduce/alleviate the effects of the size of the neointima and its affects on the human, balloon angioplasty is performed reducing the radial inward extent of the neointima. However in a substantial number of the humans receiving this procedure, restenosis of the artery occurs by migration of the smooth muscle cells to, and concentration of leucocytes carrying fat deposits at, the place of the balloon angioplasty thus increasing the radial inward extent of the neointima.
The teachings of publication WO95/26193 provide a procedure for preventing restenosis using forms of hyaluronic acid administered before, during and/or after the balloon angioplasty procedure. Suitable amounts may be administered intravenously, by injection, or subcutaneously. The form of hyaluronic acid preferably had a molecular weight of less than 750,000 daltons and in one embodiment a concentration of about 2% by weight in sterile water. Effective amounts of the form of hyaluronic acid provided in each dosage administered were from about 10 mg/70 kg human to in excess of 3000 mg/70 kg person, prior to, during and/or after the angioplasty procedure. The oral route was not given as one of the preferred routes. The reason is that persons skilled in the art generally believe that oral administration of the form of hyaluronic acid will not at least for small amounts pass the form of hyaluronic acid into the blood system from the stomach. Such persons believe that a substantial portion of any orally administered form of hyaluronan will be digested, degraded or disassociated into its smaller sugar components in the stomach by the stomach acid before a substantial amount of the form of hyaluronan (greater than K (1000) daltons) can enter the blood system. Thus according to the beliefs of pesons skilled in the art, very large dosage amounts of the form of hyaluronan would have to be administered orally for oral delivery to be effective, and even then consider it unlikely to escape the stomach as intact high molecular weight HA.
Publication WO91/04058 (Application PCT/CA90/00306) teaches the use of a minimum amount of 10 mg/70 kg person of a form of hyaluronan up to in excess of 3000 mg/70 kg person to transport medicines and/or therapeutic agents to the site in the human body in need of the treatment, with preferred amounts exceeding 50 mg/70 kg person to about 350 mg/70 kg person [Page 26, lines 32-371]. At page 18, reference is made to the proposed routes of administration. One of the routes proposed to be used is by oral administration [Page 18, line 5]. However not one of the specific examples in the document, provides specifics using the oral route. At that time oral administration was thought not to be that efficient. While the oral route may have been proposed, persons skilled in the art would believe much of the administered form of hyaluronan would not pass intact into the blood stream. Therefore persons skilled in the art would prefer the other routes for example, intravenous and direct injection when employing the teachings of the document.
Hence Applicants herein believe that oral administration of forms of hyaluronan would not be preferred by persons skilled in the art or in fact be used because to their minds there are better alternate routes. For example the routes of administration of the hyaluronic acid as taught by U.S. Pat. No. 4,808,576 are intramuscular, intravenous, subcutaneous and topical (Column 3, lines 17-18). No teaching of oral administration of hyaluronic acid is proposed as it was believed at that time (even to the present date) that oral administration would not be as good a route.
Thus Applicants believe that the preferred routes of administration to persons skilled in the art are systemic (intravenous, direct injection), subcutaneous and most recently topical. However systemic administration requires hospital or medical clinic time for administration—a costly procedure even under “out-patient” treatment conditions. If the patient in the hospital were to be treated by intravenous administration or by subcutaneous injection over for example 3-5 days, the costs can be substantial. For many conditions, topical treatment is not appropriate.
It is therefore an object of this invention to provide for the prevention and/or treatment of diseases and/or conditions by the oral administration of forms of hyaluronic acid (hyaluronan).
It is a still further object of the invention to provide orally administrable dosages containing forms of hyaluronan which allow the orally administrable form of intact hyaluronan in the stomach prior to passage into the blood stream, in a biologically active form (35,000 daltons to 2,000,000 daltons) determined by the Dextran Standard. (The conversion factor from the newer Dextran Standard to the older Protein Standard on which earlier filed applications were based, is in the order of about 3.3. The molecular weight determined under the newer Dextran Standard must be divided by 3.3 to determine the molecular weight under the older Protein Standard. Thus, the above molecular weights would be between about 11,000 daltons to about 600,000 K. daltons.)
It is a further object of the invention to provide dosages containing forms of hyaluronan for oral administration.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed discussion of embodiment thereof.
SUMMARY OF THE INVENTION
In the development of this invention, the inventors have discovered:
(a) that unexpectedly, hyaluronan when administered orally can be effective to treat and/or prevent a condition and/or disease of a human, such as prevent restenosis;
(b) that unexpectedly “more” hyaluronan is not necessarily better and that unexpectedly “less” hyaluronan may be better (for example dosage amounts between about 3 mg/kg of body weight of a human to about 100 mg/kg of a human of a form of hyaluronan and preferably between about between 3 mg/kg to about 30 mg/kg of a human and more preferably between about 3 mg/kg to about 10
Asculai Samuel S
Turley Eva A
Jagotec AG
Leydig , Voit & Mayer, Ltd.
Peselev Elli
LandOfFree
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