WO2014066622A2 - Use of collagenase to treat glaucoma - Google Patents

Use of collagenase to treat glaucoma Download PDF

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Publication number
WO2014066622A2
WO2014066622A2 PCT/US2013/066589 US2013066589W WO2014066622A2 WO 2014066622 A2 WO2014066622 A2 WO 2014066622A2 US 2013066589 W US2013066589 W US 2013066589W WO 2014066622 A2 WO2014066622 A2 WO 2014066622A2
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Prior art keywords
collagenase
couagenase
purified
eye
glaucoma
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French (fr)
Inventor
Robert HONKANEN
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Research Foundation of the State University of New York
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Research Foundation of the State University of New York
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24003—Microbial collagenase (3.4.24.3)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/00781—Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment

Definitions

  • the present invention relates generally to a method to reduce fibrosis following glaucoma surgery involving administration of purified collagenase into a patient's eye.
  • Glaucoma is a leading cause of irreversible blindness. About 60.5 million people were affected with glaucoma in 2010, with a predicted increase to approximately 79.6 million by 2020. Approximately fourteen percent of those affected with glaucoma will be bilaterally blinded. Treatments that lower intraocular pressure are common for control of glaucoma, regardless of the type of glaucoma. When medications or lasers cannot effectively control or lower the intraocular pressure to acceptable levels, surgical intervention is often necessary.
  • Glaucoma filtration surgery i.e., trabeculectomy
  • Glaucoma filtration surgery is a commonly performed type of glaucoma surgery.
  • a small opening i.e., a fistula
  • Aqueous fluid produced by the eye is thereby given an alternative pathway to leave the eye, lowering intraocular pressure.
  • steroids such as Tissue Plasminogen Activator (TPA); Betaaminopropionitrile (BAPN); D-penicillamine; daunorubicin; 5-fluorouracil; and Mitomycin C
  • TPA Tissue Plasminogen Activator
  • BAPN Betaaminopropionitrile
  • D-penicillamine D-penicillamine
  • daunorubicin 5-fluorouracil
  • Mitomycin C have been used in an effort to prevent fibrosis following surgery. However, failures readily occur with such agents.
  • Mechanical devices such as metallic shunts and collagen inserts, have also been used to improve healing from glaucoma filtration surgery. Other interventions such as radiation have also been attempted. However, mechanical devices have also been unsuccessful in preventing fibrosis and reduction of filtration.
  • seton implants are often used to help form a mechanical barrier to prevent formation of scar tissue.
  • seton implants are also subject to wound healing after implantation and failure of these devices readily occurs. Failure of seton implants is also due to formation of fibrous scar tissue surrounding the implant, which prevents adequate drainage of aqueous fluid.
  • the present invention provides a method for providing collagenase injections to relieve intraocular pressure of patients recovering from glaucoma filtration surgery and implantation of seton implants.
  • scarring and fibrous adhesions are dissolved by use of Clostridiopeptidase A derived from bacterium Clostridium histolyticum, preferably administered in an absence of triamcinolone or other corticosteroids.
  • the present invention is related to the discovery of the effectiveness of collagenase injections. That is, the present invention relates to treating a patient by injecting an effective amount of collagenase to affected regions of an eye.
  • the present invention also relates to the use of collagenase in the manufacture of a medicament to treat intraocular scarring and fibrosis occurring after glaucoma filtration surgery and after implantation of seton implants.
  • collagenase treatment has proven effective for treatment of adhesive capsulitis, also known as frozen shoulder, and for reduction of cellulite.
  • Collagenase injections have been proposed for the treatment of diseases such as Dupuytren's disease, adhesive capsulitis and Peyronie's disease, associated with collagen cords or plaques. See, U.S. Patent Nos. 5,589,171, 6,086,872,
  • Dupuytren's Disease Hand Clinics, G.M. Rayan (Ed.), W.B. Saunders 15(1), 97-107, 1999; Hurst, L.C, Badalêt, M.A. (invited editors & authorship), Dupuytren's Disease, R.
  • Collagenase is an enzyme that has specific ability to digest collagen.
  • a preferred form of a collagenase is derived from fermentation by Clostridium histolyticum and is purified by a chromatographic technique, such as that disclosed in U.S. Pat. No. 7,811 ,560 to Sabatino.
  • Collagenase naturally produced by Clostridium histolyticum once purified will exhibit two distinct peaks when run on an electrophoresis SDS gel. These two distinct peaks are referred to as collagenase I and collagenase II.
  • Collagenase ABC I microbial collagenases
  • Collagenase ABC ⁇ microbial collagenases
  • Collagenase ABC I is a single polypeptide chain consisting of approximately 1000 amino acids of known sequence. It has an observed molecular weight of 115 kiloDalton (kD), an isoelectric point (pi) between 5.63 - 5.68, and an extinction coefficient of 1.480. From its activity behavior toward synthetic substrate, it has been determined that Collagenase ABC I is class I Clostridium histolyticum collagenase. Collagenase ABC II is also a single polypeptide chain consisting of about 1000 amino acids of deduced sequence. It has an observed molecular weight of 110 kD, an isoelectric point between 5.46 - 5.57 and an extinction coefficient of 1.576. Collagenase ABC II functionally belongs to the class II Clostridium histolyticum collagenase.
  • the drug substance may have a one to one mass ratio for collagenase ABC I and ABC II with an extinction coefficient of 1.528. Both collagenases require tightly bound zinc and loosely bound calcium for their activity. Collagenase ABC I and Collagenase ABC II are not
  • Lyophilized collagen for injection is purified clostridial collagenase prepared as a lyophilized formulation and may contain about 0.1 mg lactose monohydrate USP per 1,000 ABC units of collagenase activity.
  • a preferred collagenase composition includes a mixture of collagenase I and collagenase
  • SRC unit II in a mass ratio of about one to one and having specific activity from about 500 SRC units/mg to about 15,000 SRC units/mg, preferably of at least about 700 SRC units/mg, more preferably of at least about 1000 SRC units/mg, more preferably at least about 1500 SRC units/mg.
  • One SRC unit will solubilize rat tail collagen into ninhydrin reaction material equivalent to 1 nanomole of leucine per minute, at 25 degrees C, pH 7.4.
  • Collagenase has been described in ABC units as well, with 10,000 ABC of approximately 0.58mg.
  • the potency assay of collagenase is based on the digestion of undenatured collagen (from bovine tendon) at pH 7.2 and 37 degrees C for 20-24 hours.
  • Collagenase administration in the present invention is preferably via injection in a pharmaceutically acceptable liquid carrier.
  • the carrier does not interact or deactivate the collagenase. Examples are normal saline and aqueous NaCl/CaCl 2 buffer containing 0.9%
  • Treatment of scarring and fibrosis occurring after glaucoma filtration surgery and implantation of seton implants using the present invention is a non-surgical procedure in which collagenase injection is directed at an eye of a patient.
  • collagenase is injected into an anterior chamber of the eye.
  • the anterior chamber of the eye includes one of a sub-Tenons and an episcleral space of the eye.
  • Injection of collagenase into the sub-Tenons and episcleral space of the eye prevents and reverses fibrosis and formation of scar tissue. Removal of fibrotic tissue and scar tissue present in the sub-Tenons and episcleral space of the eye re-opens a fistula tract of the eye that was previously opened by the glaucoma filtration surgery.
  • Advantages of the present inventive technology are that it is minimally invasive, does not require any extended rehabilitation and/or surgery and would return patients to normal activities or daily living.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Engineering & Computer Science (AREA)
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Description

USE OF COLLAGENASE TO TREAT GLAUCOMA
PRIORITY
This application claims priority to U.S. Provisional Patent Application No. 61/717,837, filed on October 24, 2012, the contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention:
The present invention relates generally to a method to reduce fibrosis following glaucoma surgery involving administration of purified collagenase into a patient's eye.
2. Description of the Related Art:
Glaucoma is a leading cause of irreversible blindness. About 60.5 million people were affected with glaucoma in 2010, with a predicted increase to approximately 79.6 million by 2020. Approximately fourteen percent of those affected with glaucoma will be bilaterally blinded. Treatments that lower intraocular pressure are common for control of glaucoma, regardless of the type of glaucoma. When medications or lasers cannot effectively control or lower the intraocular pressure to acceptable levels, surgical intervention is often necessary.
Glaucoma filtration surgery, i.e., trabeculectomy, is a commonly performed type of glaucoma surgery. In glaucoma filtration surgery, a small opening, i.e., a fistula, is created between an anterior chamber of an eye including a subconjunctival and a sub-Tenon's space of the eye. Aqueous fluid produced by the eye is thereby given an alternative pathway to leave the eye, lowering intraocular pressure.
As a result of glaucoma filtration surgery, however, scarring and fibrosis develops at the subconjunctival and sub-Tenon's tissues. Scarring and fibrosis develops following collagen deposition in the area of the glaucoma filtration surgery. The scarring and fibrosis often results in a gradual reduction of filtration and loss of control of intraocular pressure. Moreover, surgical failures occur in up to 30% of cases. Histologic examination of filtration operations resulting in scarring has shown that obstruction to filtration occurs at the subconjunctival tissues including the Tenons capsule and episcleral tissues. Multiple efforts aimed at improving the healing process have been attempted.
Pharmaceutical agents including steroids, such as Tissue Plasminogen Activator (TPA); Betaaminopropionitrile (BAPN); D-penicillamine; daunorubicin; 5-fluorouracil; and Mitomycin C, have been used in an effort to prevent fibrosis following surgery. However, failures readily occur with such agents.
Mechanical devices, such as metallic shunts and collagen inserts, have also been used to improve healing from glaucoma filtration surgery. Other interventions such as radiation have also been attempted. However, mechanical devices have also been unsuccessful in preventing fibrosis and reduction of filtration.
When glaucoma filtration fails, seton implants are often used to help form a mechanical barrier to prevent formation of scar tissue. However, seton implants are also subject to wound healing after implantation and failure of these devices readily occurs. Failure of seton implants is also due to formation of fibrous scar tissue surrounding the implant, which prevents adequate drainage of aqueous fluid.
SUMMARY OF THE INVENTION
The present invention provides a method for providing collagenase injections to relieve intraocular pressure of patients recovering from glaucoma filtration surgery and implantation of seton implants.
In a preferred embodiment, scarring and fibrous adhesions are dissolved by use of Clostridiopeptidase A derived from bacterium Clostridium histolyticum, preferably administered in an absence of triamcinolone or other corticosteroids.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is related to the discovery of the effectiveness of collagenase injections. That is, the present invention relates to treating a patient by injecting an effective amount of collagenase to affected regions of an eye. The present invention also relates to the use of collagenase in the manufacture of a medicament to treat intraocular scarring and fibrosis occurring after glaucoma filtration surgery and after implantation of seton implants.
As described in U.S. Patent Application Serial Nos. 11/335,157 and 11/703,269, published as U.S. Publ. No. 2006-0204488 Al and 2007-0224184 Al, respectively, collagenase treatment has proven effective for treatment of adhesive capsulitis, also known as frozen shoulder, and for reduction of cellulite. Collagenase injections have been proposed for the treatment of diseases such as Dupuytren's disease, adhesive capsulitis and Peyronie's disease, associated with collagen cords or plaques. See, U.S. Patent Nos. 5,589,171, 6,086,872,
6,022,539, of Wegman. The published work of Dr. Badalamente, in Dupuytren's disease forms the rationale for the present invention (Starkweather, K., Lattuga, S., Hurst, L.C, Badalamente, M.A., Guilak, F., Sampson, S.P., Dowd, A., Wisch, D. Collagenase in the Treatment of Dupuytren's Disease: An in vitro Study. J. Hand Surg. 21A:490-95, 1996; Badalamente, M.A., Hurst, L.C, Enzyme Injection as a Non-operative Treatment for Dupuytren's Disease, J. Drug-Delivery 3(l):35-40, 1996; Hurst, L.C, Badalamente, M.A. (invited authorship) Non-operative Treatment of
Dupuytren's Disease, Hand Clinics, G.M. Rayan (Ed.), W.B. Saunders 15(1), 97-107, 1999; Hurst, L.C, Badalamente, M.A. (invited editors & authorship), Dupuytren's Disease, R.
Tubinana, R. Tubiana, C. Leclercq, L.C. Hurst, M.A. Badalamente (eds), Martin Dunitz
Publisher, London (2000); Badalamente, M.A., Hurst, L.C. Enzyme Injection as a Non-operative Treatment of Dupuytren's Disease, J. Hands Surg. 25A(4);629-36, 2000; Badalamente, M.A., Hurst, L.C, Hentz, V.R. Collagen as a Clinical Target: Non-operative Treatment of Dupuytren's Disease. J. Hand Surg. 27A(5):788-98, 2002, Badalamente, M.A., Hurst, L.C, Efficacy and Safety of Injectable Mixed Collagenase Subtypes in the Treatment of Dupuytren's Contracture, J. Hand. Surg. 32A(6): 767-774, (2007). In Dupuytren's disease, the pathognomonic fibrous cord is often interspersed with a septa-like arrangement of adipose tissue. These present clinically as mattress-type "lumps" of varying sizes, and in Dupuytren's disease, are termed nodules. It has been a consistent clinical finding in both Phase 2 and 3 trials for Dupuytren's disease that after purified Clostridial collagenase injection, not only does the collagenous cord dissolve and rupture when subjected to pressure in extension, but the fibro-fatty nodules also resolve, and harmlessly resorb. Therefore, collagenase injected subcutaneously into afflicted areas was postulated to be a safe and effective treatment.
Collagenase is an enzyme that has specific ability to digest collagen. A preferred form of a collagenase is derived from fermentation by Clostridium histolyticum and is purified by a chromatographic technique, such as that disclosed in U.S. Pat. No. 7,811 ,560 to Sabatino.
Collagenase naturally produced by Clostridium histolyticum once purified will exhibit two distinct peaks when run on an electrophoresis SDS gel. These two distinct peaks are referred to as collagenase I and collagenase II.
One form of purified collagenase used for injection includes two microbial collagenases, referred to as "Collagenase ABC I" and "Collagenase ABC Π". Both collagenases are isolated and purified from the fermentation of the bacterium Clostridium histolyticum and belong to the same metalloprotease.
Collagenase ABC I is a single polypeptide chain consisting of approximately 1000 amino acids of known sequence. It has an observed molecular weight of 115 kiloDalton (kD), an isoelectric point (pi) between 5.63 - 5.68, and an extinction coefficient of 1.480. From its activity behavior toward synthetic substrate, it has been determined that Collagenase ABC I is class I Clostridium histolyticum collagenase. Collagenase ABC II is also a single polypeptide chain consisting of about 1000 amino acids of deduced sequence. It has an observed molecular weight of 110 kD, an isoelectric point between 5.46 - 5.57 and an extinction coefficient of 1.576. Collagenase ABC II functionally belongs to the class II Clostridium histolyticum collagenase.
The drug substance may have a one to one mass ratio for collagenase ABC I and ABC II with an extinction coefficient of 1.528. Both collagenases require tightly bound zinc and loosely bound calcium for their activity. Collagenase ABC I and Collagenase ABC II are not
immunologically crossreactive and have a very broad hydrolyzing reactivity toward all types of collagen. Even though each collagenase shows different specificity, together they show synergistic activity toward collagen.
Lyophilized collagen for injection is purified clostridial collagenase prepared as a lyophilized formulation and may contain about 0.1 mg lactose monohydrate USP per 1,000 ABC units of collagenase activity.
A preferred collagenase composition includes a mixture of collagenase I and collagenase
II in a mass ratio of about one to one and having specific activity from about 500 SRC units/mg to about 15,000 SRC units/mg, preferably of at least about 700 SRC units/mg, more preferably of at least about 1000 SRC units/mg, more preferably at least about 1500 SRC units/mg. One SRC unit will solubilize rat tail collagen into ninhydrin reaction material equivalent to 1 nanomole of leucine per minute, at 25 degrees C, pH 7.4. Collagenase has been described in ABC units as well, with 10,000 ABC of approximately 0.58mg. The potency assay of collagenase is based on the digestion of undenatured collagen (from bovine tendon) at pH 7.2 and 37 degrees C for 20-24 hours. The number of peptide bonds cleaved are measured by reaction with ninhydrin. Amino groups released by a solubilized digestion control are subtracted. One net ABC unit of collagenase will solubilize ninhydrin reactive material equivalent to 1.09 nanomoles of leucine per minute. One SRC unit equals approximately 6.3 ABC units. Collagenase administration in the present invention is preferably via injection in a pharmaceutically acceptable liquid carrier. Preferably, the carrier does not interact or deactivate the collagenase. Examples are normal saline and aqueous NaCl/CaCl2 buffer containing 0.9%
Figure imgf000006_0001
Treatment of scarring and fibrosis occurring after glaucoma filtration surgery and implantation of seton implants using the present invention is a non-surgical procedure in which collagenase injection is directed at an eye of a patient. In an embodiment of the present invention, collagenase is injected into an anterior chamber of the eye. The anterior chamber of the eye includes one of a sub-Tenons and an episcleral space of the eye. Injection of collagenase into the sub-Tenons and episcleral space of the eye prevents and reverses fibrosis and formation of scar tissue. Removal of fibrotic tissue and scar tissue present in the sub-Tenons and episcleral space of the eye re-opens a fistula tract of the eye that was previously opened by the glaucoma filtration surgery.
Advantages of the present inventive technology are that it is minimally invasive, does not require any extended rehabilitation and/or surgery and would return patients to normal activities or daily living.
While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

WHAT IS CLAIMED:
1. A method of treatment for reducing fibrosis, the method comprising:
administering an effective amount of purified coUagenase into an anterior chamber of an eye.
2. The method of claim 1, wherein the treatment is administered following glaucoma surgery.
3. The method of claim 1, wherein the anterior chamber is a sub-Tenons space of the eye.
4. The method of claim 1, wherein the anterior chamber is an episcleral space of the eye.
5. The method of claim 1, wherein the purified coUagenase is Clostridiopeptidase A derived from bacterium Clostridium histolyticum.
6. The method of claim 1, wherein purified coUagenase is administered alone.
7. The method of claim 1, wherein purified coUagenase is administered in an absence of traimcinolone or other corticosteroids.
8. The method of claim 1, wherein the purified coUagenase is injected in a dose comprising at least about 15,000 SRC units/mg, applied in one or more injections.
9. The method of claim 1, wherein the purified coUagenase is injected in a volume of about 1.0 ml.
10. The method of claim 1, wherein the purified coUagenase comprises one of coUagenase I and coUagenase II.
PCT/US2013/066589 2012-10-24 2013-10-24 Use of collagenase to treat glaucoma Ceased WO2014066622A2 (en)

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