Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1992-07-09
2001-08-07
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S912000, C514S054000, C424S678000, C424S681000
Reexamination Certificate
active
06271216
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a stable visco-elastic physiologic balanced salt solution of a hyaluronate salt such as sodium hyaluronate which contains both calcium ion and magnesium ion (but no phosphates) to achieve physiologic compatibility.
BACKGROUND OF THE INVENTION
Over the last 20 years there has been a growing awareness of the importance of the use of ionically and osmotically balanced irrigation solutions during intra-ocular surgeries. Originally, all that was available for this purpose was simple sterile saline. While saline was useful as an irrigating solution it was subsequently recognized that the lack of proper salt balance was damaging to the intra-ocular tissues. Over the years different formulations for irrigating solutions had been developed in an attempt to provide more physiologically compatible solutions.
A big advance from simple saline solution was the introduction of phosphate buffered solutions which provided both osmotic balance and pH control. While phosphate buffered saline solutions represented a major step towards less toxic irrigation fluids, they were not completely physiologic and thus produced some cytotoxic effects since they did not contain the requisite balance of salts.
Phosphate buffered saline was soon replaced by balanced salt solutions which were both ionically and osmotically balanced. In addition to sodium chloride, these solutions contained potassium chloride, calcium chloride, magnesium chloride, sodium acetate and sodium citrate. Such balanced salt solutions were judged to be more physiologically compatible with ocular tissue than simple saline or phosphate buffered saline solutions since they contained the essential ions for normal cell metabolism. Various publications in the medical literature have demonstrated the superiority of balanced salt formulations over simple saline or phosphate buffered saline solutions, such as:
1. Edelhauser, H. F., Van Horn, D. L., Hyndiuk, R. A., Schultz, R. O., “Intraocular Irrigating Solutions: Their Effect on the Corneal Endothelium,” Arch. Ophthalmol., 93: 648, 1975.
2. Edelhauser, H. F., Van Horn, D. L., Schultz, R. O., Hyndiuk, R. A., “Comparative Toxicity of Intraocular Irrigating Solutions on the Corneal Endothelium”, Am. J. Ophthalmol., 81: 473, 1976.
3. Moorhead, L. C., Redburn, D. A., Merritt, J., Garcia, C. A., “The Effects of Intravitreal Irrigation During Vitrectomy on the Electroretinogram,” Am. J. Ophthalmol., 88: 239, 1979.
In the development of visco-elastic hyaluronate formulations as medical devices for ophthalmic surgical procedures, it is important that they contain a physiologic balance of salt to minimize toxicity. Although the importance of such a physiologically balanced visco-elastic formulation is well recognized among the ophthalmic community, as of yet none of the commercially available hyaluronate products provide complete physiologic balanced formulations. Dr. James McCulley in Ocular Surgery News, August, 1987, summarizes the importance of physiologic balanced media as follows:
“The cells require electrolytes. If these electrolytes are not present, one start[s] to see toxicity or apparent toxicity and cellular changes. The absence of calcium caused by viscoelastic substances is a major potential problem.
‘All of the currently available viscoelastics are made in calcium-free solvents. That apparently is necessary because of the stability of the viscoelastic preparations. If calcium is present in the formulation then it is apparently difficult to maintain the substances in solution, so calcium is removed.
‘We're facing a situation where not only calcium, but magnesium and other critical ions are not present. The cells can do fine without nutrients for a short period, but they don't do well without the ions.”
Three commercially available hyaluronates for use in ophthalmic surgery are as follows:
a. Healon—each ml of Bealon contains 10 mg of sodium hyaluronate, 8.5 mg of sodium chloride, 0.28 mg of disodium dihydrogen phosphate dihydrate, 0.04 mg of sodium dihydrogen phosphate hydrate and q.s. water for injection USP.
Denlinger, J. L., et al., “Replacement of the Liquid Vitreus with Sodium Hyaluronate in Monkeys,” Exp. Eye Res. (1980) 31, 81-99, 101-117, disclose that Healon contains sodium hyaluronate (10±1 mg/ml) “dissolved in a physiological balanced salt solution” (0.145 mg/ml NaCl, 0.34 mg/ml NaH
2
PO
4
; and 1.5 mg/ml Na
2
HPO
4
; pH=7.2±0.2). The term “balanced salt solution” thus refers to an isotonic saline buffered with phosphate.
b. Amvisc—each ml of Amvisc contains 10 mg of sodium hyaluronate adjusted to yield approximately 40,000 centistokes, 9.0 mg of sodium chloride and sterile water for injection USPQS.
c. Viscoat—each 1 ml of Viscoat solution contains not more than 40 mg of sodium chondroitin sulfate, 30 mg sodium hyaluronate, 0.45 mg sodium dihydrogen phosphate hydrate, 2.00 mg disodium hydrogen phosphate, 4.3 mg sodium chloride (with water for injection USP grade, qs).
None of these three products contained the essential ions, in particular magnesium and calcium, which are judged critical for physiologic compatibility. Without these essential ions there can be significant cytotoxicity to the corneal endothelium (corneal cells).
There is available a balanced salt solution marketed by Alcon Labs which is a physiologic irrigation solution for use during various surgical procedures of the eye, ear, nose and/or throat and is listed in the 1988 PDR for ophthalmology as:
BSS is a sterile physiological balanced salt solution of sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl
2
.2H
2
O), magnesium chloride (MgCl
2
.6H
2
O), sodium acetate (C
2
H
3
NaO
2
.3H
2
O), and sodium citrate dihydrate (C
6
H
5
Na
3
O
7
.2H
2
O). BSS is isotonic to the tissues of the eyes. It is a lint-free solution containing essential ions for normal cell metabolism. Each ml contains sodium chloride 0.64%, potassium chloride 0.075%, calcium chloride 0.048%, magnesium chloride 0.03%, sodium acetate 0.39%, sodium citrate 0.17%, sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection.
The above % may be converted to mg/ml by multiplying each by 10.
The above balanced salt solution has never been used or suggested for use with sodium hyaluronate.
Until now, where it has been attempted to prepare sodium hyaluronate in a balanced salt solution containing calcium ion and magnesium ion, it has been found that the sodium hyaluronate solution was not stable.
DESCRIPTION OF THE INVENTION
In accordance with the present invention, a sterile, stable, isotonic, visco-elastic, non-toxic, physiologic, osmotically balanced salt solution of a hyaluronate salt is provided, in which the hyaluronate salt remains in solution, which contains a hyaluronate salt, such as sodium hyaluronate, sodium ion, chloride ion, potassium ion, calcium ion, magnesium ion, acetate ion, citrate ion and water, at a pH of about 7.3±0.3.
The sodium ion, potassium ion, calcium ion and magnesium ion will be preferably present as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, respectively, while the acetate and citrate will preferably be present as sodium acetate and sodium citrate, respectively. However, these ions may take the form of other salts in lieu of or in addition to the above salts, such as potassium citrate, sodium citrate, calcium citrate, potassium acetate, magnesium acetate, magnesium citrate and the like, provided that the concentration of Na ion, K ion, Ca ion, Mg ion, and citrate are within the teachings of the present invention as defined herein.
For each ml of the balanced salt solution of the invention, the sodium hyaluronate employed will have a molecular weight within the range of from about 0.2×10
6
to about 10.0×10
6
, and preferably from about 0.25×10
6
to about 4.0×10
6
, and is present in an amount within the range of from about 0.1% to about 5% by weight, and preferably from about 1.0% to about 3.0% by weight. Other forms o
Beaty Narlin B.
Mello Robert J.
Tew William P.
Allergan
Fay Zohreh
Stout, Uxa, Buyan & Mullins
Uxa Frank J.
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