Article of manufacture comprising local anesthetic, buffer, and glycosaminoglycan in syringe with improved stability
An article of manufacture according to the present invention comprises a composition including a glycosaminoglycan, a local anesthetic, and a buffer packaged in a syringe or vial constructed from either glass or a plastic selected from the group consisting of cyclic olefin polymer, cyclic olefin copolymer, or high density non-nucleated polypropylene. The composition has unexpectedly improved stability on storage. The composition can be formulated for treatment of a urinary tract disease or condition, such as interstitial cystitis, also known as bladder pain syndrome or hypersensitive bladder syndrome.
1 . An article of manufacture comprising a terminally-sterilized aqueous liquid composition including:
(a) an anionic polysaccharide, selected from the group consisting of: hyaluronic acid, chondroitin sulfate, pentosan polysulfate, dermatan sulfate, heparin, heparan sulfate, and keratan sulfate;
(b) a local anesthetic, wherein the local anesthetic is selected from the group consisting of bupivacaine, mepivacaine, prilocaine, ropivacaine, dibucaine and a combination thereof; and
(c) a buffer selected from the group consisting of phosphate buffer, bicarbonate buffer, Tris (Tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine (N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO (piperazine-N,N′-bis(2-hydroxypropaneulfonic acid) buffer, 2TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, and a combination thereof, wherein the components of (a), (b), and (c) form a composition; and
(d) a container comprising a syringe or vial that is compatible with sterilization by heat, wherein the container packages the composition formed by the components of (a), (b), and (c), wherein the container is constructed of a plastic selected from the group consisting of cyclic olefin polymer plastic, and cyclic olefin copolymer plastic;
wherein the pH of the aqueous liquid composition is between 6.8 and 8.2, and wherein stability of the local anesthetic, when tested after the sterilization by heat and after 12 months of storage, results in a content of local anesthetic in the aqueous solution that is at least 95% of the local anesthetic originally present in the aqueous liquid composition.
2 . The article of claim 1 wherein the heparinoid is heparin.
3 . The article of manufacture of claim 2 wherein the heparinoid is heparin and wherein the heparin is heparin sodium.
4 . The article of manufacture of claim 2 wherein a unit dose of the composition included in the article of manufacture comprises from about 1000 units of heparin to about 250,000 units of heparin per unit dose of the aqueous liquid composition.
5 . The article of manufacture of claim 4 wherein a unit dose of the aqueous liquid composition included in the article of manufacture comprises about 40,000 units of heparin, about 50,000 units of heparin, or about 60,000 units of heparin.
6 . The article of manufacture of claim 1 wherein the buffer is selected from the group consisting of phosphate buffer, bicarbonate buffer, Tris buffer, and a combination thereof.
7 . The article of manufacture of claim 6 wherein the buffer is phosphate buffer and the phosphate buffer is sodium phosphate buffer.
8 . The article of manufacture of claim 6 wherein the buffer is bicarbonate buffer and the bicarbonate buffer is sodium bicarbonate buffer.
9 . The article of manufacture of claim 6 wherein the buffer is Tris buffer.
10 . The article of manufacture of claim 1 wherein the aqueous liquid composition comprises an additional component selected from the group consisting of:
(a) an osmolar component that provides an isotonic or nearly isotonic solution compatible with human cells and blood;
(b) a compound that enables persistence of the composition to the surface of the bladder epithelium in a quantity sufficient to treat, ameliorate, or prevent a lower urinary tract disorder;
(c) an antibacterial agent in a quantity sufficient to treat, ameliorate, or prevent a lower urinary tract disorder;
(d) an antifungal agent in a quantity sufficient to treat, ameliorate, or prevent a lower urinary tract disorder;
(e) a vasoconstrictor in a quantity sufficient to treat, ameliorate, or prevent a lower urinary tract disorder;
(f) a preservative; and
(g) an anti-inflammatory agent.
11 . The article of manufacture of claim 1 wherein the pH of the aqueous liquid composition is from about 7.2 to about 7.6.
12 . The article of manufacture of claim 11 wherein the pH of the aqueous liquid composition is about 7.5.
13 . The article of manufacture of claim 1 wherein the aqueous liquid composition is formulated for treating a lower urinary tract disorder selected from the group consisting of bacterial cystitis, fungal/yeast cystitis, vulvar vestibulitis, vulvodynia, dyspareunia, urethral syndrome, and endometriosis in women; prostatitis and chronic pelvic pain syndrome in men; and radiation-induced cystitis, chemotherapy-induced cystitis, interstitial cystitis (bladder pain syndrome or hypersensitive bladder syndrome), and overactive bladder in men or women.
14 . The article of manufacture of claim 13 wherein the aqueous liquid composition is formulated for treating interstitial cystitis (bladder pain syndrome or hypersensitive bladder syndrome).
15 . The article of manufacture of claim 1 wherein the container is a syringe.
16 . The article of manufacture of claim 1 wherein the syringe comprises a barrel and the interior of the barrel of the syringe comprises a siloxane coating to reduce deposition of the local anesthetic on the syringe, or wherein the interior of the vial comprises a siloxane coating, wherein the siloxane coating reduces deposition of the local anesthetic on the syringe or vial.
17 . The article of manufacture of claim 1 wherein the aqueous liquid composition consists of the anionic polysaccharide, the local anesthetic and the buffer.