OpkoDD Little-Known Fact: heparin-derived oligosaccharides
Jan 6, 2017 14:58:30 GMT
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Post by Uncle on Jan 6, 2017 14:58:30 GMT
OpkoDD Little-Known Fact: heparin-derived oligosaccharides
heparin-derived oligosaccharides
Asthma & COPD
OPKO owns global rights to a heparin-derived oligosaccharide intended for therapeutic use in asthma and COPD (chronic obstructive pulmonary disease). It is expected to demonstrate decreased side effects and improved efficacy as compared to current medications.
Initial studies, using sheep and mouse asthma models, have demonstrated successful anti-inflammatory and anti-allergic activity when administered orally or inhaled with inhalers or nebulizers. Human feasibility studies for asthma have also proven successful.
Hypersulfated disaccharides to treat elastase related disorders
Publication: WO 2012058424 A1
Patent: Application number PCT/US2011/058085
Inventors William Abraham, Tahir Ahmed
Applicant Opko Health, Inc
Hypersulfated disaccharides of formula I and other hypersulfated disaccharides disclosed herein are used to treat diseases or conditions associated with human neutrophil elastase imbalances. The disaccharides and/or intermediates useful to prepare such compounds are prepared from heparin. The diseases and conditions which are treated with a compound of formula I include chronic obstructive pulmonary disorder (COPD) and cystic fibrosis (CF). The formulations are delivered to the lungs in an aerosol formulation or dry powder means or via nebulization. Oral forms are also suitable.
The present invention relates to the use of a hypersulfated disaccharide compound of formula I as further described below and other hypersulfated disaccharides as disclosed herein in the treatment of diseases or conditions associated with leukocyte elastase. In particular, the present invention relates to formulations of a compound of formula I to improve lung function (tracheal mucous velocity) and/or to treat/mitigate diseases or conditions such as chronic obstructive pulmonary disease (COPD) and/or cystic fibrosis (CF). COPD has been described as a "quiet killer" because of its slow progression and the fact that it is often untreated during the early course of the disease.
Emphysema and chronic bronchitis are sub-types of COPD. In emphysema, the walls of the alveoli are structurally damaged which ultimately reduces the surface area for gas exchange and lung
capacity. Chronic bronchitis is characterized by excessive mucous production and airflow limitations develop with disease progression. Patients with COPD have significant airflow limitations and
eventually lose the ability to adequately oxygenate the blood. COPD is a leading cause of death worldwide and the rate of COPD-related deaths is rising. New England . of Med. Sep. 16, 2010.
Progressive loss of lung function, a hallmark of COPD, is not prevented by currently available therapy. There is thus a severe need for drugs or effective treatments for this disease.
Hypersulfated disaccharides and methods of using the same for the treatment of inflammations
US 20030087875 A1
Application number US 10/123,979
Inventors Tahir Ahmed, Gregory Smith
Provided are compounds and compositions thereof that are useful for treating information, particularly pulmonary inflammations including asthma and asthma-related pathologies such as allergy. Also provided are methods for using such compounds and compositions of the invention to treat patients suffering from, or predisposed to develop inflammation.
Update:
Hypersulfated disaccharide formulations
US 20160250242 A1
Publication number: US20160250242 A1
Publication type: Application
Application number: US 15/153,962
Publication date: Sep 1, 2016
Filing date May 13, 2016
Inventors: Tahir Ahmed
Original Assignee: Opko Health, Inc.
CROSS REFERENCE TO RELATED APPLICATION
This application is a Continuation of U.S. application Ser. No. 14/011,807 filed on Aug. 28, 2013, now U.S. Pat. No. 9,006,211, which is a Continuation of U.S. application Ser. No. 12/953,831 filed on Nov. 24, 2010, now U.S. Pat. No. 8,546,351, which claims priority to U.S. Provisional Application No. 61/266,361 filed on Dec. 3, 2009, which are all incorporated herein to by reference in their entireties.
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations comprising a hypersulfated disaccharide compound of formula I as further described below and a delivery agent selected from a
pharmaceutically acceptable vehicle (additive) that facilitates/enhances oral delivery of said compounds. The formulations are useful in the treatment of a variety of inflammatory disorders and
diseases in animals and people, and, in particular, pulmonary disorders selected from asthma and other conditions or diseases associated with inflammation of the lungs and airway.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 7,056,898 (the '898 patent) discloses and claims certain hypersulfated disaccharides and methods of using same to treat certain inflammatory disorders. This patent specifically
describes the use of the claimed compounds to treat pulmonary inflammations including asthma and asthma-related pathologies, such as allergic reactions or an inflammatory disease or condition.
The compounds disclosed therein are described as being capable of preventing, reversing and/or alleviating the symptoms of asthma and asthma-related pathologies, particularly the late phase
response in asthma patients following antigen stimulation. The examples and figures shown therein specifically relate to intravenous and inhalation means of administration of the recited
disaccharides. In the '898 patent there is a general disclosure of the oral administration of a hypersulfated disaccharide designated as 811-25-1 at a dose of 0.5 mgs/kg to sheep, but no specific data is shown.
There is also no disclosure therein of any specific oral formulation nor any specific disclosure of any data related to administration of a specific oral formulation. There is a need for an improved pulmonary or anti-inflammatory medication that can be delivered in small dosages to patients in need of treatment thereof on a convenient basis and which does not have the side effects associated with, for example, chronic administration of steroids or leukotriene receptor antagonists such as montelukast sodium.
The inventor has met this unmet need and has surprisingly found that certain formulations comprising the hypersulfated disaccharides recited herein and a delivery agent selected from the group consisting of a pharmaceutically acceptable natural or synthetic polymer as well as other vehicles that heretofore have been utilized to improve delivery of large compounds (e.g., those compounds having molecular weights of greater than 4,500 daltons as average molecular weight) have enhanced absorption/bioavailability/efficacy relative to the same compounds delivered without the claimed additives.
While the literature has disclosed that certain carbomers enhance the intestinal absorption of Low Molecular Weight Heparins (LMWH) having molecular weights of approximately 4500 daltons, there has been no teaching or suggestion of the use of such materials to enhance the absorption of low molecular weight disaccharides. In fact, as reported in Thanou et al., Pharmaceutical Research, 18 (11) 2001, such carbomers were added because of the large size of the LMWHs which, it was thought, would have difficulty permeating across the intestinal epithelium via transcellular or paracellular routes (via passage through the tight junction) albeit with less difficulty than fractions having a molecular weight of 12,000 daltons.
The same would not apply to low molecular disaccharides which are, when compared to LMWHs, small molecules which can more readily permeate across the intestinal epithelium. The present inventors have unexpectedly found that low molecular weight disaccharides, in particular, low molecular weight hypersulfated disaccharides (e.g., of about 1,000 daltons), have surprisingly better efficacy when combined with a polymeric material having at least one of the chemical and/or physical properties of, for example, Carbopol 934 P and/or other carbomers. Such polymers have ionic groups such as a carboxylic acid side chain and/or hydrophilic moieties which facilitate the delivery of the hypersulfated disaccharides of the invention.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical formulations comprising a compound of formula I and pharmaceutically acceptable salts thereof and a delivery agent selected from the group
consisting of a pharmaceutically acceptable synthetic polymer or natural polymer, an oligomer or other agent that facilitates the delivery or administration of a compound of formula I into the
bloodstream of an animal. The compound in the formulation is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and R6 are independently
selected from the group consisting of H, SO3H or PO3H and provided that at least two of R1-R6 is selected from SO3H or PO3H. The present invention also relates to formulations having a
compound of formula I wherein at least three of R1-R6 are selected from SO3H or PO3H.
The present invention further relates to formulations having compounds of formula I wherein at least four of R1-R6 are selected from SO3H or PO3H. The present invention further relates to formulations having compounds of formula I wherein at least five of R1-R6 are selected from SO3H or PO3H.
The present invention preferably relates to a compound of formula I and pharmaceutically acceptable salts thereof wherein R1-R6 are selected from SO3H. The present invention also relates to
formulations having a compound of formula I wherein R1-R6 are independently selected from SO3H or PO3H. The invention further includes pro-drugs, derivatives, active metabolites, partially
ionized and fully ionized derivatives of the compounds of formula I and stereoisomers thereof. The monomers which make up the disaccharides of the invention may be D or L isomers and the
hydroxyl moieties or sulfated or phosphated versions thereof around the carbocyclic ring (or acyclic versions or intermediates thereof) may have the alpha or beta designation at any particular
stereocenter.
The linking oxygen atom between the monosaccharide moieties may also be alpha or beta. The molecular weight of the compounds of the invention is typically less than 1,000 daltons.
The present invention also relates to a pharmaceutical formulation comprising (i) a compound of formula I and pharmaceutically acceptable salts thereof wherein R1, R2, R4, R5 and R6 are
independently selected from H, SO3H or PO3H and R3 is independently selected from SO3H or PO3H and (ii) an additive selected from the group consisting of a pharmaceutically acceptable
natural or synthetic polymer.
OPKO Scientific Advisory Board Member on heparin-derived oligosaccharides
Tahir Ahmed, M.D.
Dr. Ahmed is Director of Pulmonary Research at Mount Sinai Medical Center, Miami Beach, FL. He graduated from King Edward Medical College, Lahore, in 1973 and completed an Internal
Medicine residency and fellowship in pulmonary diseases at Mount Sinai Medical Center. He joined the faculty of at both Mount Sinai Medical Center and University of Miami School of Medicine in 1979. He was an Assistant Associate Professor of Medicine at University of Miami from 1980 to 1992 and Professor of Medicine from 1992 to 2006. He also served as Chief of the Pulmonary
Division at Mount Sinai Medical Center from 1996 to 2006. His research work has included pathophysiology of pulmonary circulation and bronchial asthma. He is the author of over 80 scientific
publications. His current research is focused on studying the anti-inflammatory activity of heparin-derived oligosaccharides.
In Retrospect:
On 22 May 2014 OPKO Health, Inc. (FL, USA) made public that it had completed its acquisition of Inspiro Medical Ltd (Misgav, Israel) that it first announced on 17 April 2014. The Israeli
company has developed a dry powder inhaler called Inspiromatic™. It employs an internal microcontroller and flow sensor coupled with micropump technology to disperse the drug particles at the correct velocity and enable the delivery of drugs at flow rates as low as 6 L/min. The inhaler is fitted with a green or red flashing light to inform the patient if inhalation has been successful and a beeper to indicate that the dose has been delivered. The construction also includes a built-in logger that stores inhalation data allowing later downloading and review by doctors. OPKO plans to use the inhaler to administer its heparin-derived oligosaccharide candidate for the treatment of asthma and chronic obstructive pulmonary disease.
Ref:
www.opko.com/therapeutics/asthma-copd/
www.google.com/patents/WO2012058424A1
www.opko.com/about-us/scientific-advisory-board/
www.google.com/patents/US20030087875
www.freshpatents.com/-dt20160901ptan20160250242.php
www.google.com/patents/US20160250242
opkodd.wordpress.com/2015/07/28/in-retrospect-opko-inspiromatic-the-smart-inhaler/
heparin-derived oligosaccharides
Asthma & COPD
OPKO owns global rights to a heparin-derived oligosaccharide intended for therapeutic use in asthma and COPD (chronic obstructive pulmonary disease). It is expected to demonstrate decreased side effects and improved efficacy as compared to current medications.
Initial studies, using sheep and mouse asthma models, have demonstrated successful anti-inflammatory and anti-allergic activity when administered orally or inhaled with inhalers or nebulizers. Human feasibility studies for asthma have also proven successful.
Hypersulfated disaccharides to treat elastase related disorders
Publication: WO 2012058424 A1
Patent: Application number PCT/US2011/058085
Inventors William Abraham, Tahir Ahmed
Applicant Opko Health, Inc
Hypersulfated disaccharides of formula I and other hypersulfated disaccharides disclosed herein are used to treat diseases or conditions associated with human neutrophil elastase imbalances. The disaccharides and/or intermediates useful to prepare such compounds are prepared from heparin. The diseases and conditions which are treated with a compound of formula I include chronic obstructive pulmonary disorder (COPD) and cystic fibrosis (CF). The formulations are delivered to the lungs in an aerosol formulation or dry powder means or via nebulization. Oral forms are also suitable.
The present invention relates to the use of a hypersulfated disaccharide compound of formula I as further described below and other hypersulfated disaccharides as disclosed herein in the treatment of diseases or conditions associated with leukocyte elastase. In particular, the present invention relates to formulations of a compound of formula I to improve lung function (tracheal mucous velocity) and/or to treat/mitigate diseases or conditions such as chronic obstructive pulmonary disease (COPD) and/or cystic fibrosis (CF). COPD has been described as a "quiet killer" because of its slow progression and the fact that it is often untreated during the early course of the disease.
Emphysema and chronic bronchitis are sub-types of COPD. In emphysema, the walls of the alveoli are structurally damaged which ultimately reduces the surface area for gas exchange and lung
capacity. Chronic bronchitis is characterized by excessive mucous production and airflow limitations develop with disease progression. Patients with COPD have significant airflow limitations and
eventually lose the ability to adequately oxygenate the blood. COPD is a leading cause of death worldwide and the rate of COPD-related deaths is rising. New England . of Med. Sep. 16, 2010.
Progressive loss of lung function, a hallmark of COPD, is not prevented by currently available therapy. There is thus a severe need for drugs or effective treatments for this disease.
Hypersulfated disaccharides and methods of using the same for the treatment of inflammations
US 20030087875 A1
Application number US 10/123,979
Inventors Tahir Ahmed, Gregory Smith
Provided are compounds and compositions thereof that are useful for treating information, particularly pulmonary inflammations including asthma and asthma-related pathologies such as allergy. Also provided are methods for using such compounds and compositions of the invention to treat patients suffering from, or predisposed to develop inflammation.
Update:
Hypersulfated disaccharide formulations
US 20160250242 A1
Publication number: US20160250242 A1
Publication type: Application
Application number: US 15/153,962
Publication date: Sep 1, 2016
Filing date May 13, 2016
Inventors: Tahir Ahmed
Original Assignee: Opko Health, Inc.
CROSS REFERENCE TO RELATED APPLICATION
This application is a Continuation of U.S. application Ser. No. 14/011,807 filed on Aug. 28, 2013, now U.S. Pat. No. 9,006,211, which is a Continuation of U.S. application Ser. No. 12/953,831 filed on Nov. 24, 2010, now U.S. Pat. No. 8,546,351, which claims priority to U.S. Provisional Application No. 61/266,361 filed on Dec. 3, 2009, which are all incorporated herein to by reference in their entireties.
FIELD OF THE INVENTION
The present invention relates to pharmaceutical formulations comprising a hypersulfated disaccharide compound of formula I as further described below and a delivery agent selected from a
pharmaceutically acceptable vehicle (additive) that facilitates/enhances oral delivery of said compounds. The formulations are useful in the treatment of a variety of inflammatory disorders and
diseases in animals and people, and, in particular, pulmonary disorders selected from asthma and other conditions or diseases associated with inflammation of the lungs and airway.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 7,056,898 (the '898 patent) discloses and claims certain hypersulfated disaccharides and methods of using same to treat certain inflammatory disorders. This patent specifically
describes the use of the claimed compounds to treat pulmonary inflammations including asthma and asthma-related pathologies, such as allergic reactions or an inflammatory disease or condition.
The compounds disclosed therein are described as being capable of preventing, reversing and/or alleviating the symptoms of asthma and asthma-related pathologies, particularly the late phase
response in asthma patients following antigen stimulation. The examples and figures shown therein specifically relate to intravenous and inhalation means of administration of the recited
disaccharides. In the '898 patent there is a general disclosure of the oral administration of a hypersulfated disaccharide designated as 811-25-1 at a dose of 0.5 mgs/kg to sheep, but no specific data is shown.
There is also no disclosure therein of any specific oral formulation nor any specific disclosure of any data related to administration of a specific oral formulation. There is a need for an improved pulmonary or anti-inflammatory medication that can be delivered in small dosages to patients in need of treatment thereof on a convenient basis and which does not have the side effects associated with, for example, chronic administration of steroids or leukotriene receptor antagonists such as montelukast sodium.
The inventor has met this unmet need and has surprisingly found that certain formulations comprising the hypersulfated disaccharides recited herein and a delivery agent selected from the group consisting of a pharmaceutically acceptable natural or synthetic polymer as well as other vehicles that heretofore have been utilized to improve delivery of large compounds (e.g., those compounds having molecular weights of greater than 4,500 daltons as average molecular weight) have enhanced absorption/bioavailability/efficacy relative to the same compounds delivered without the claimed additives.
While the literature has disclosed that certain carbomers enhance the intestinal absorption of Low Molecular Weight Heparins (LMWH) having molecular weights of approximately 4500 daltons, there has been no teaching or suggestion of the use of such materials to enhance the absorption of low molecular weight disaccharides. In fact, as reported in Thanou et al., Pharmaceutical Research, 18 (11) 2001, such carbomers were added because of the large size of the LMWHs which, it was thought, would have difficulty permeating across the intestinal epithelium via transcellular or paracellular routes (via passage through the tight junction) albeit with less difficulty than fractions having a molecular weight of 12,000 daltons.
The same would not apply to low molecular disaccharides which are, when compared to LMWHs, small molecules which can more readily permeate across the intestinal epithelium. The present inventors have unexpectedly found that low molecular weight disaccharides, in particular, low molecular weight hypersulfated disaccharides (e.g., of about 1,000 daltons), have surprisingly better efficacy when combined with a polymeric material having at least one of the chemical and/or physical properties of, for example, Carbopol 934 P and/or other carbomers. Such polymers have ionic groups such as a carboxylic acid side chain and/or hydrophilic moieties which facilitate the delivery of the hypersulfated disaccharides of the invention.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical formulations comprising a compound of formula I and pharmaceutically acceptable salts thereof and a delivery agent selected from the group
consisting of a pharmaceutically acceptable synthetic polymer or natural polymer, an oligomer or other agent that facilitates the delivery or administration of a compound of formula I into the
bloodstream of an animal. The compound in the formulation is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5 and R6 are independently
selected from the group consisting of H, SO3H or PO3H and provided that at least two of R1-R6 is selected from SO3H or PO3H. The present invention also relates to formulations having a
compound of formula I wherein at least three of R1-R6 are selected from SO3H or PO3H.
The present invention further relates to formulations having compounds of formula I wherein at least four of R1-R6 are selected from SO3H or PO3H. The present invention further relates to formulations having compounds of formula I wherein at least five of R1-R6 are selected from SO3H or PO3H.
The present invention preferably relates to a compound of formula I and pharmaceutically acceptable salts thereof wherein R1-R6 are selected from SO3H. The present invention also relates to
formulations having a compound of formula I wherein R1-R6 are independently selected from SO3H or PO3H. The invention further includes pro-drugs, derivatives, active metabolites, partially
ionized and fully ionized derivatives of the compounds of formula I and stereoisomers thereof. The monomers which make up the disaccharides of the invention may be D or L isomers and the
hydroxyl moieties or sulfated or phosphated versions thereof around the carbocyclic ring (or acyclic versions or intermediates thereof) may have the alpha or beta designation at any particular
stereocenter.
The linking oxygen atom between the monosaccharide moieties may also be alpha or beta. The molecular weight of the compounds of the invention is typically less than 1,000 daltons.
The present invention also relates to a pharmaceutical formulation comprising (i) a compound of formula I and pharmaceutically acceptable salts thereof wherein R1, R2, R4, R5 and R6 are
independently selected from H, SO3H or PO3H and R3 is independently selected from SO3H or PO3H and (ii) an additive selected from the group consisting of a pharmaceutically acceptable
natural or synthetic polymer.
OPKO Scientific Advisory Board Member on heparin-derived oligosaccharides
Tahir Ahmed, M.D.
Dr. Ahmed is Director of Pulmonary Research at Mount Sinai Medical Center, Miami Beach, FL. He graduated from King Edward Medical College, Lahore, in 1973 and completed an Internal
Medicine residency and fellowship in pulmonary diseases at Mount Sinai Medical Center. He joined the faculty of at both Mount Sinai Medical Center and University of Miami School of Medicine in 1979. He was an Assistant Associate Professor of Medicine at University of Miami from 1980 to 1992 and Professor of Medicine from 1992 to 2006. He also served as Chief of the Pulmonary
Division at Mount Sinai Medical Center from 1996 to 2006. His research work has included pathophysiology of pulmonary circulation and bronchial asthma. He is the author of over 80 scientific
publications. His current research is focused on studying the anti-inflammatory activity of heparin-derived oligosaccharides.
In Retrospect:
On 22 May 2014 OPKO Health, Inc. (FL, USA) made public that it had completed its acquisition of Inspiro Medical Ltd (Misgav, Israel) that it first announced on 17 April 2014. The Israeli
company has developed a dry powder inhaler called Inspiromatic™. It employs an internal microcontroller and flow sensor coupled with micropump technology to disperse the drug particles at the correct velocity and enable the delivery of drugs at flow rates as low as 6 L/min. The inhaler is fitted with a green or red flashing light to inform the patient if inhalation has been successful and a beeper to indicate that the dose has been delivered. The construction also includes a built-in logger that stores inhalation data allowing later downloading and review by doctors. OPKO plans to use the inhaler to administer its heparin-derived oligosaccharide candidate for the treatment of asthma and chronic obstructive pulmonary disease.
Ref:
www.opko.com/therapeutics/asthma-copd/
www.google.com/patents/WO2012058424A1
www.opko.com/about-us/scientific-advisory-board/
www.google.com/patents/US20030087875
www.freshpatents.com/-dt20160901ptan20160250242.php
www.google.com/patents/US20160250242
opkodd.wordpress.com/2015/07/28/in-retrospect-opko-inspiromatic-the-smart-inhaler/