WO1999030717A1 - Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire - Google Patents
Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire Download PDFInfo
- Publication number
- WO1999030717A1 WO1999030717A1 PCT/US1998/025481 US9825481W WO9930717A1 WO 1999030717 A1 WO1999030717 A1 WO 1999030717A1 US 9825481 W US9825481 W US 9825481W WO 9930717 A1 WO9930717 A1 WO 9930717A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- brinzolamide
- blood flow
- ocular
- medicament
- manufacture
- Prior art date
Links
- 229960000722 brinzolamide Drugs 0.000 title claims abstract description 33
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 title claims abstract description 32
- 239000003814 drug Substances 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 230000004386 ocular blood flow Effects 0.000 title abstract description 12
- 230000001965 increasing effect Effects 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 230000017531 blood circulation Effects 0.000 claims description 32
- 208000010412 Glaucoma Diseases 0.000 claims description 6
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 4
- 206010029113 Neovascularisation Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 238000009472 formulation Methods 0.000 abstract description 5
- 210000003733 optic disk Anatomy 0.000 description 24
- 230000000699 topical effect Effects 0.000 description 16
- 229960003933 dorzolamide Drugs 0.000 description 11
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 11
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 210000001525 retina Anatomy 0.000 description 6
- 241000282326 Felis catus Species 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000002207 retinal effect Effects 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- 206010021143 Hypoxia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960000571 acetazolamide Drugs 0.000 description 3
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229960004083 methazolamide Drugs 0.000 description 3
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010067013 Normal tension glaucoma Diseases 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000002491 angiogenic effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 210000004155 blood-retinal barrier Anatomy 0.000 description 2
- 230000004378 blood-retinal barrier Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- BORBLDJNKYHVJP-FXBDTBDDSA-N dolichodial Chemical compound C[C@H]1CC[C@H](C(=C)C=O)[C@@H]1C=O BORBLDJNKYHVJP-FXBDTBDDSA-N 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 201000002978 low tension glaucoma Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 201000006366 primary open angle glaucoma Diseases 0.000 description 2
- 210000001957 retinal vein Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000006442 vascular tone Effects 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 1
- 238000012935 Averaging Methods 0.000 description 1
- 102100024633 Carbonic anhydrase 2 Human genes 0.000 description 1
- 101710167917 Carbonic anhydrase 2 Proteins 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- 206010048964 Carotid artery occlusion Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 101000760643 Homo sapiens Carbonic anhydrase 2 Proteins 0.000 description 1
- 206010065630 Iris neovascularisation Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 208000007135 Retinal Neovascularization Diseases 0.000 description 1
- NOSIYYJFMPDDSA-UHFFFAOYSA-N acepromazine Chemical compound C1=C(C(C)=O)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 NOSIYYJFMPDDSA-UHFFFAOYSA-N 0.000 description 1
- 229960005054 acepromazine Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 102000057327 human CA2 Human genes 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229940100654 ophthalmic suspension Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004895 regional blood flow Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000001927 retinal artery Anatomy 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Definitions
- the present invention is directed to the topical ophthalmic use of brinzolamide to improve ocular blood flow.
- Brinzolamide is disclosed in commonly assigned U.S. Patent Nos. 5,240,923 and 5,378,703 for its usefulness in controlling intraocular pressure, particularly in the treatment of glaucoma. These patents are incorporated herein by reference.
- the present invention is directed to the topical use of brinzolamide formulations to improve ocular blood flow, such as to ocular tissues including the optic nerve head.
- the distribution coefficients for methazolamide, acetazolamide and dorzolamide are 0.64, 0.23, and 1.72 respectively.
- the IC 50 values (determined against human carbonic anhydrase II) are 12.5 nM, 9.04 nM, and 3.74 nM respectively.
- the Ki values are 29.3 nM, 33.8 nM, and 0.51 nM respectively.
- Dorzolamide is significantly more potent than either acetazolamide or methazolamide as measured by Ki and IC 50 and is only slightly, ⁇ 2x, more lipophilic as measured by its distribution coefficient. Thus, it is not expected to efficiently cross the blood retinal barrier. None of these compounds have the requisite characteristics to efficiently improve ocular blood flow. Thus there is a need to identify superior agents to improve blood flow to the back of the eye.
- brinzolamide is well suited to penetrate into the retina, choroid, and optic nerve head upon topical ocular administration. Moreover, brinzolamide significantly increases blood flow to the back of the eye and in particular the optic nerve head.
- Brinzolamide (R-(+)-4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H- thieno[3,2,e]l-2-thiazine-6-sulfonamide- 1,1 -dioxide, is a carbonic anhydrase inhibitor which has been found to be effective in lowering the elevated intraocular pressure associated with ocular hypertension and glaucoma.
- the distribution coefficient, IC 50 and Ki values for brinzolamide are 6-56, 3.19 nM and 0.13 nM respectively. Further studies discussed in the examples show that it penetrates to the back of the eye following topical ocular delivery and is also effective in increasing blood flow in ocular tissues including the optic nerve head.
- Ocular diseases and conditions which find their etiology in compromised blood flow can be treated with brinzolamide.
- These diseases and conditions include glaucoma including but not limited to primary open angle glaucoma (POAG) and normal tension glaucoma also known as low tension glaucoma or angle closure glaucoma, occlusion conditions, such as, branch vein occlusion and retinal artery or vein occlusion, diabetic retinopathy, and retinal or iris neovascularization from any cause.
- POAG primary open angle glaucoma
- normal tension glaucoma also known as low tension glaucoma or angle closure glaucoma
- occlusion conditions such as, branch vein occlusion and retinal artery or vein occlusion, diabetic retinopathy, and retinal or iris neovascularization from any cause.
- Neovascularization of the retinal, choroidal, or iridial tissues arises by the action of angiogenic substance(s).
- these angiogenic substances are produced in ocular tissue which is suffering from hypoxia.
- hypoxia hypoxia
- Brinzolamide is preferably formulated as a topical ophthalmic suspension with a pH of about 4.5-7.8. It will normally be contained in the formulation at a concentration of 0.1%- 10% by weight, preferably 0.25%-5.0% by weight. Thus, for topical presentation 1-3 drops of these formulations would be delivered to the surface of the eye 1-4 times a day according to the routine discretion of a skilled clinician.
- Example 4 describes the tissue distribution of brinzolamide in the eyes of rabbits.
- ONH blood flow was then measured by LDF in the anesthetized, spontaneously breathing felines. The experiment was repeated after a one-week interval in the same cats to assess the reproducibility of the technique. Averaging the two blood flow measurements showed that ONH flow was increased by an average of 21.8% over that measured in the control group. In anesthetized, ventilated cats, ONH blood flow was increased on average 16.5% + 8% at 60 minutes following a single topical dose. Intravenous brinzolamide produced a 46 + 17% increase (p ⁇ _0.05) in ONH blood flow; ONH vascular resistance, a measure of vascular tone in the ONH microcirculation, was reduced by 35 + 8% (p ⁇ 0.05).
- Intravenous administration of 0.5, 2.5, and 5 mg/kg of brinzolamide to anesthetized, ventilated New Zealand albino rabbits produced a significant dose-related increase in total ocular blood which reflected increases in blood flow to the tissues of the eye measured by the colored microsphere technique.
- Optic nerve head blood flow, measured by LDF was also increased above baseline.
- Ocular vascular tone was reduced since total ocular vascular resistance was decreased dose-dependently.
- Baseline blood flow was 657 + 36 ⁇ l/min in the hypofused eye.
- Intravenous doses of brinzolamide produced similar increases in total ocular blood flows of 29%, 68%, and 90% in normal eyes and increases of 21%, 64%, and 90% in hypofused eyes.
- the highest intravenous brinzolamide dose returned regional blood flows to the hypofused eye to baseline levels found in the normal eye. Percentage wise, the blood flow increase to the hypofused eye was greatest to iridial, ciliary, and choroidal tissues, respectively.
- LDF Baseline values for optic nerve head (ONH) blood flow, blood pressure, heart rate, intraocular pressure (IOP), and acid-base balance were determined before treatment began and 7-14 days after completion of a treatment arm; baseline values for the measured variables did not significantly change during the experiment. Treatment measurements were made 90 minutes after the last dose on day eight. Optic nerve head blood flow and measured systemic variables were not changed by vehicle treatment. Minimal disturbance of acid-base balance occurred in brinzolamide treated animals. IOP was decreased by 16.8 + 2.2% (p ⁇ 0.05 versus vehicle; p ⁇ .001 versus baseline) and ONH blood flow was significantly increased by 11.2 + 1.6% (mean + SEM; p ⁇ 0.05) following topical brinzolamide.
- the tissue distribution of brinzolamide was determined in New Zealand Albino (NZW) and Dutch belted rabbits after a single topical ocular dose of 1 % 14 C- brinzolamide.
- NZW New Zealand Albino
- Dutch belted rabbits after a single topical ocular dose of 1 % 14 C- brinzolamide.
- brinzolamide was found to slowly redistribute into the retina.
- the T max values in the retina were 20 days and 36 days in the NZW and Dutch belted rabbits respectively. These data demonstrate that brinzolamide is slowly delivered to the retina over time and likely comes for the red blood cells.
- the C max values were 0.330 and 0.338 ⁇ g equivalents/g in the NZW and Dutch belted rabbits respectively.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Cette invention se rapporte à des procédés et à des formulations servant à augmenter le flux sanguin oculaire en utilisant du brinzolamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU18012/99A AU1801299A (en) | 1997-12-12 | 1998-12-01 | Use of brinzolamide for the manufacture of a medicament for improving ocular blood flow |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6965697P | 1997-12-12 | 1997-12-12 | |
| US60/069,656 | 1997-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999030717A1 true WO1999030717A1 (fr) | 1999-06-24 |
Family
ID=22090398
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1998/025481 WO1999030717A1 (fr) | 1997-12-12 | 1998-12-01 | Utilisation de brinzolamide pour la production d'un medicament servant a ameliorer le flux sanguin oculaire |
Country Status (4)
| Country | Link |
|---|---|
| AR (1) | AR015494A1 (fr) |
| AU (1) | AU1801299A (fr) |
| WO (1) | WO1999030717A1 (fr) |
| ZA (1) | ZA9811387B (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6753009B2 (en) | 2002-03-13 | 2004-06-22 | Mcneil-Ppc, Inc. | Soft tablet containing high molecular weight polyethylene oxide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5378703A (en) * | 1990-04-09 | 1995-01-03 | Alcon Laboratories, Inc. | Sulfonamides useful as carbonic anhydrase inhibitors |
| WO1996037203A1 (fr) * | 1995-05-22 | 1996-11-28 | Advanced Research & Technology Institute | Procede d'augmentation du debit sanguin retinien |
-
1998
- 1998-12-01 AU AU18012/99A patent/AU1801299A/en not_active Abandoned
- 1998-12-01 WO PCT/US1998/025481 patent/WO1999030717A1/fr active Application Filing
- 1998-12-11 ZA ZA9811387A patent/ZA9811387B/xx unknown
- 1998-12-11 AR ARP980106315A patent/AR015494A1/es unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5378703A (en) * | 1990-04-09 | 1995-01-03 | Alcon Laboratories, Inc. | Sulfonamides useful as carbonic anhydrase inhibitors |
| WO1996037203A1 (fr) * | 1995-05-22 | 1996-11-28 | Advanced Research & Technology Institute | Procede d'augmentation du debit sanguin retinien |
Non-Patent Citations (2)
| Title |
|---|
| C.CAMRAS: "A triple-masked primary therapy study of the efficacy and safety of BID and TID-dosed brinzolamide 1% compared to TID-dosed dorzolamide 2% and BID-dosed timolol 0.5%", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 38, no. 4, 15 March 1997 (1997-03-15), pages s560, XP002092853 * |
| T.DEAN ET AL.: "Brinzolamide (AL-8462) suspension is a new topically active carbonic anhydrase inhibitor in the dutch-belted rabbit and cynomolgus monkey", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 38, no. 4, 15 March 1997 (1997-03-15), pages S813, XP002092854 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6753009B2 (en) | 2002-03-13 | 2004-06-22 | Mcneil-Ppc, Inc. | Soft tablet containing high molecular weight polyethylene oxide |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1801299A (en) | 1999-07-05 |
| AR015494A1 (es) | 2001-05-02 |
| ZA9811387B (en) | 1999-07-14 |
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