CA2131130A1 - Modulation of cellular activity - Google Patents
Modulation of cellular activityInfo
- Publication number
- CA2131130A1 CA2131130A1 CA002131130A CA2131130A CA2131130A1 CA 2131130 A1 CA2131130 A1 CA 2131130A1 CA 002131130 A CA002131130 A CA 002131130A CA 2131130 A CA2131130 A CA 2131130A CA 2131130 A1 CA2131130 A1 CA 2131130A1
- Authority
- CA
- Canada
- Prior art keywords
- daltons
- hyaluronic acid
- fractions
- agent
- human
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
Abstract
A method for the modulation of cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM-1, HARLEC, CD44, and RHAMM) of a human is provided the method comprising the administration of a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
Description
213tttt30 TITLE OF INVENTION
Modulation of Cellular Activity FIELD OF INVENTION
This invention relates to the modulation of cellular activity and particularly to the modulation of cellular activity in a human employing forms of hyaluronic acid, including specific molecular fractions of, for example, sodium hyaluronate.
BACKGROUND OF INVENTION
Cell adhesion molecules, which were originally thought to be mere glue that hold cells together in tissues, are now also thought to have a wider contribution to the function of the human body. In this regard, see BIOTECH GETSA GRIP ON CELL ADHESION, SCIENCE, Volume 260 (May 14, 1993).
Novel therapies have been proposed based on these cell adhesion molecules. One class of endothelial adhesion molecules referred to includes the endothelial adhesion molecule ICAM-1. This molecule (ICAM-1) was discovered to carry the human rhinoviruses (which cause about 50% of colds) into the body's cells. The rhinoviruses enter the body's cells by latching on to the adhesion molecule ICAM- 1.
By using soluble ICAM- 1 as a decoy, it was proposed that the infection of the cells can be blocked. However, soluable ICAM just was not very sticky and therefore, the proposal has not reached the market.
Genetic engineering techniques have been used to fuse antibody fragments to rhinovirus - binding portions of ICAM- 1 in an attempt to discover a preventian for the common cold.
Another adhesion molecule, CD44, is found normally on Iymphocytes.
The CD44 adhesion molecule also studs the surface of pancreatic tumour cells that are metastatic. The CD44 molecules may have inadvertently disguised the cancer cells and allows them to circulate freely in the bloodstream.
It has now been discovered that adhesion molecule ICAM- 1 is a cell--2- ~13113~
surface receptor for hyaluronic acid (hyaluronan) . ICAM- 1 is expressed (produced and put on the cell surface) in the liver endothelial cells and corneal epitheleum cells. ICAM-1 is overexpressed in inflamm~tion, cancer and infection.
HARLEC (Hyaluronic Acid [Hyaluronan] Receptors Liver Endothelial 5 Cells) is also a cell-surface receptor for Hyaluronan and is also expressed (produced and put on the cell surface) in liver endothelial cells and corneal epithelial cells. (This Inventor believes the two to be one and the same adhesion molecule or, at the very least, so intimately related to be one another as to be close to being one and the same.) The molecules CD44 and RHAMM (_eceptor for HA-Mediated Motility) are also cell-surface receptors for hyaluronic acid (hyaluronan).
It is therefore an object of the invention to provide new methods of treatment of disease and conditions, new uses for forms of hyaluronic acid (hyaluronan) (HA), new dosage amounts of pharmaceutical compositions and new pharmaceutical compositions suitable for use in such treatments and uses of forms of HA.
Further and other objects of the invention will be realized to those skilled in the art from the following summary of the invention and description.
SUMMARY OF INVENTION
According to one aspect of the invention, a method for the modulation of cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM- 1, HARLEC, CD44, and RHAMM) of a human is provided the method comprising the administration of a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, -3- ~ 0 complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues and/orcells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
Thus, for example, where an inflammatory response (reaction) may be set up in the area of damage or trauma, the response may include the migration of inflammatory cells (for example, neutrophils, macrophages, and other white blood cells) to the area. The damage caused by setting up the inflammatory response may be greater than the actual damage or trauma caused.
The administration of the form of hyaluronic acid will bind to the HA receptor of the adhesion molecule, thus modulating the body's response and thus, subsequent and consequent damage.
Drugs for the treatment of the disease and for condition may also accompany the form of hyaluronic acid in which event the drug enhances the modulation of the form of the HA activity. The form of HA further targets the drug to the adhesion molecule (for example, ICAM- l, HARLEC, RHAMM, and CD44) .
Suitable drugs may comprise for example, a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenT M contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolT M ) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixT M ), 4 ~131 13~
immunosuppressants (for example cyclosporins), Iymphokynes (such as interleukin - 2 and the like), alpha-and-B-interferon, and the like.
According to another aspect of the invention, use of a form of hyaluronic acid, for example, hyaluronic acid, a salt thereof (for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons), molecular fractions thereof [for example, those disclosed in Canadian Letters Patent 1205031 (to FIDIA) such as those from 50,000- 100,000 daltons, 250,000-350,000 daltons and 500,000-730,000, daltons or other fractions]
homologues, analogues, derivatives, complexes, esters, fragments and/or subunitsof hyaluronic acid and/or combinations thereof is provided to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body. The form of hyaiuronic acid may be used with pharmaceutically tolerable carrier (for example, sterile water). Once again, tissue or cell modulation is enhanced in a person when suffering a disease and/or condition. The HA binds to the HA receptors of the adhesion molecule. Once again, the form of HA may be used with a suitable drug (as described previously). Both the form of HA and drug are in effective non-toxic amounts.
The form of HA may also be used to prevent a disease or condition (such as a cold) by preventing the human rhinovirus from entering the body's cells by the form of HA binding with the ICAM- 1 adhesion molecules (instead of the Rhinovirus binding or latching on).
Thus, according to another aspect of the invention, Applicant provides a novel method of preventing a disease and/or condition, the method comprising administering an effective non-toxic amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons] molecular weight fractions of a form of sodium hyaluronate [forexample, fractions disclosed in Canadian Letters Patent 125031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons or other fractions], homologues, analogues, derivatives, complexes, esters, fragments and/or subunits of hyaluronic acid and/or combinations thereof to a human to modulate celluar activity of tissues and/or cells expressing an adhesion molecule in the human body to thereby prevent a disease or condition. The 5 administration of the form of HA is preferably in a pharmaceutically tolerable carrier (for example, sterile water). Thus, for example, the common cold may be prevented. Drugs which may assist to prevent a disease or condition may be adminstered with the form of hyaluronic acid (HA). Thus, for example, acetylsalicylic acid may be administered with a form of HA for the prevention of 10 stroke.
The administration of the form of hyaluronic acid (HA) thus inhibits cellular adhesion and/or modulates cellular activity. in a human The HA binds to the HA receptors of the adhesion molecule. Thus, the administration of the form of hyaluronic acid will bind to the HA receptor of the adhesion molecule, thus 15 preventing the disease or condition (for example, preventing the binding of the rhinovirus to the adhesion molecule ICAM- 1 thereby preventing the rhinovirus entering the body's cells by latching onto the adhesion molecule ICAM- 1.
Where drugs are taken for the prevention of a disease and for condition may. as discussed above, may accompany the form of hyaluronic acid 20 used to prevent the disease or condition. For example, for the prevention of a stroke, people today take acetylsalicylic acid (aspirin) in an effective amount.
The drug may be accompanied by a suitable form of hyaluronic acid in an effective non-toxic amount. Thus, the taking of the two together will, it is believed, reduce the risk of stroke even more than the individual taking aspirin 25 alone. The form of HA further targets the drug to the areas in need of treatment while the HA binds with the adhesion molecule (for example, ICAM- 1, HARLEC, RHAMM, and CD44) modulating their activity.
The administration may be given, among other methods, intravenously, intra-arterially, intraperitoneally, intrapleurally, - 6 ~ 2~131 130 percutaneously. (intra-cutaneously - into the skin (for example, targeting the epidermis) by topical application of effective amounts and by application to the mucasa by topical application for example, intranasally) rectally (for example, in the form of an enema or by topical application of specific areas in the rectum), 5 and by direct injection.
Where the form of hyaluronic acid is to be administered, varying effective doses may be employed - for example, 10 to lOOOmg/70kg. person with optimal doses tending to range between 50 and 500mg/70kg. person. As there is no toxicity in humans, the hyaluronic acid can obviously be administered in a dose excess (for example 3000mg/70kg. individual) without any adverse effects.
Where the administration is topical (for example, applied to the skin or mucosa), in excess of 5 mg per cm2 (square centimetre) of skin or exposed tissue (including mucosa) of the form of hyaluronic acid, shculd be applied.
With respect to the treatment of pain, preferably a minimum of 15 lOmg per cm2 (lOmg/cm2) of the form of HA should be applied topically.
Thus, effective dosage amounts contain at least about lOmg of the form of hyaluronic acid per 70kg person to in excess of lOOOmg per 70kg person where the administration is non-topical. When an NSAID for example, indomethacin (dissolved in n-methyl glucamine) or other NSAID is administered 20 with greater than 200mg hyaluronic acid for example, sodium hyaluronate per 70kg person with 1 - 2 mg/kg body weight of the person, of the NSAID (in one instance indomethacin and NMG), no major toxic side effects occur such as gastro-intestinal distress, neurological abnormalities, depression, etc., even at elevated amounts of indomethacin (if necessary). If the amount of hyaluronic acid is 25 decreased below that amount, the usual side effects may begin to reoccur. Where administration is topical, the dosage amounts contain at least about 5mg of the form of hyaluronic acid / cm2 of the skin, mucosa or tissue to which the dosage amount is to be applied.
The Drugs accompanying the form of hyaluronic acid are adjusted - 7 - ~3113l~
with the form of treatment to be an effective non-toxic amount thereof.
One form of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub units of hyaluronic acid, preferably hyaluronic acid and salts and thereof 5 suitable for use with Applicant's invention is a fraction suppied by Hyal Pharmaceutical Corporation. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3). The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000 daltons. The fraction also contains water q.s. which is triple distilled and sterile in accordance 10 with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, 15 and sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from 20 the group consisting of the following:
i ) a molecular weight within the range of 150,000-225,000;
ii) less than about 1.25% sulphated mucopolysaccharides on a total weight basis;
iii) less than about 0.6% proten on a total weight basis;
i v ) less than about 150 ppm iron on a total weight basis;
v ) less than about 15 ppm lead on a total weight basis;
v i ) less than 0.0025% glucosamine;
vii) less than 0.025% glucuronic acid;
v i i i ) les s than 0.025 % N-acetylglucosamine;
Modulation of Cellular Activity FIELD OF INVENTION
This invention relates to the modulation of cellular activity and particularly to the modulation of cellular activity in a human employing forms of hyaluronic acid, including specific molecular fractions of, for example, sodium hyaluronate.
BACKGROUND OF INVENTION
Cell adhesion molecules, which were originally thought to be mere glue that hold cells together in tissues, are now also thought to have a wider contribution to the function of the human body. In this regard, see BIOTECH GETSA GRIP ON CELL ADHESION, SCIENCE, Volume 260 (May 14, 1993).
Novel therapies have been proposed based on these cell adhesion molecules. One class of endothelial adhesion molecules referred to includes the endothelial adhesion molecule ICAM-1. This molecule (ICAM-1) was discovered to carry the human rhinoviruses (which cause about 50% of colds) into the body's cells. The rhinoviruses enter the body's cells by latching on to the adhesion molecule ICAM- 1.
By using soluble ICAM- 1 as a decoy, it was proposed that the infection of the cells can be blocked. However, soluable ICAM just was not very sticky and therefore, the proposal has not reached the market.
Genetic engineering techniques have been used to fuse antibody fragments to rhinovirus - binding portions of ICAM- 1 in an attempt to discover a preventian for the common cold.
Another adhesion molecule, CD44, is found normally on Iymphocytes.
The CD44 adhesion molecule also studs the surface of pancreatic tumour cells that are metastatic. The CD44 molecules may have inadvertently disguised the cancer cells and allows them to circulate freely in the bloodstream.
It has now been discovered that adhesion molecule ICAM- 1 is a cell--2- ~13113~
surface receptor for hyaluronic acid (hyaluronan) . ICAM- 1 is expressed (produced and put on the cell surface) in the liver endothelial cells and corneal epitheleum cells. ICAM-1 is overexpressed in inflamm~tion, cancer and infection.
HARLEC (Hyaluronic Acid [Hyaluronan] Receptors Liver Endothelial 5 Cells) is also a cell-surface receptor for Hyaluronan and is also expressed (produced and put on the cell surface) in liver endothelial cells and corneal epithelial cells. (This Inventor believes the two to be one and the same adhesion molecule or, at the very least, so intimately related to be one another as to be close to being one and the same.) The molecules CD44 and RHAMM (_eceptor for HA-Mediated Motility) are also cell-surface receptors for hyaluronic acid (hyaluronan).
It is therefore an object of the invention to provide new methods of treatment of disease and conditions, new uses for forms of hyaluronic acid (hyaluronan) (HA), new dosage amounts of pharmaceutical compositions and new pharmaceutical compositions suitable for use in such treatments and uses of forms of HA.
Further and other objects of the invention will be realized to those skilled in the art from the following summary of the invention and description.
SUMMARY OF INVENTION
According to one aspect of the invention, a method for the modulation of cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM- 1, HARLEC, CD44, and RHAMM) of a human is provided the method comprising the administration of a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, -3- ~ 0 complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues and/orcells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
Thus, for example, where an inflammatory response (reaction) may be set up in the area of damage or trauma, the response may include the migration of inflammatory cells (for example, neutrophils, macrophages, and other white blood cells) to the area. The damage caused by setting up the inflammatory response may be greater than the actual damage or trauma caused.
The administration of the form of hyaluronic acid will bind to the HA receptor of the adhesion molecule, thus modulating the body's response and thus, subsequent and consequent damage.
Drugs for the treatment of the disease and for condition may also accompany the form of hyaluronic acid in which event the drug enhances the modulation of the form of the HA activity. The form of HA further targets the drug to the adhesion molecule (for example, ICAM- l, HARLEC, RHAMM, and CD44) .
Suitable drugs may comprise for example, a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenT M contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolT M ) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixT M ), 4 ~131 13~
immunosuppressants (for example cyclosporins), Iymphokynes (such as interleukin - 2 and the like), alpha-and-B-interferon, and the like.
According to another aspect of the invention, use of a form of hyaluronic acid, for example, hyaluronic acid, a salt thereof (for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons), molecular fractions thereof [for example, those disclosed in Canadian Letters Patent 1205031 (to FIDIA) such as those from 50,000- 100,000 daltons, 250,000-350,000 daltons and 500,000-730,000, daltons or other fractions]
homologues, analogues, derivatives, complexes, esters, fragments and/or subunitsof hyaluronic acid and/or combinations thereof is provided to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body. The form of hyaiuronic acid may be used with pharmaceutically tolerable carrier (for example, sterile water). Once again, tissue or cell modulation is enhanced in a person when suffering a disease and/or condition. The HA binds to the HA receptors of the adhesion molecule. Once again, the form of HA may be used with a suitable drug (as described previously). Both the form of HA and drug are in effective non-toxic amounts.
The form of HA may also be used to prevent a disease or condition (such as a cold) by preventing the human rhinovirus from entering the body's cells by the form of HA binding with the ICAM- 1 adhesion molecules (instead of the Rhinovirus binding or latching on).
Thus, according to another aspect of the invention, Applicant provides a novel method of preventing a disease and/or condition, the method comprising administering an effective non-toxic amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons] molecular weight fractions of a form of sodium hyaluronate [forexample, fractions disclosed in Canadian Letters Patent 125031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons or other fractions], homologues, analogues, derivatives, complexes, esters, fragments and/or subunits of hyaluronic acid and/or combinations thereof to a human to modulate celluar activity of tissues and/or cells expressing an adhesion molecule in the human body to thereby prevent a disease or condition. The 5 administration of the form of HA is preferably in a pharmaceutically tolerable carrier (for example, sterile water). Thus, for example, the common cold may be prevented. Drugs which may assist to prevent a disease or condition may be adminstered with the form of hyaluronic acid (HA). Thus, for example, acetylsalicylic acid may be administered with a form of HA for the prevention of 10 stroke.
The administration of the form of hyaluronic acid (HA) thus inhibits cellular adhesion and/or modulates cellular activity. in a human The HA binds to the HA receptors of the adhesion molecule. Thus, the administration of the form of hyaluronic acid will bind to the HA receptor of the adhesion molecule, thus 15 preventing the disease or condition (for example, preventing the binding of the rhinovirus to the adhesion molecule ICAM- 1 thereby preventing the rhinovirus entering the body's cells by latching onto the adhesion molecule ICAM- 1.
Where drugs are taken for the prevention of a disease and for condition may. as discussed above, may accompany the form of hyaluronic acid 20 used to prevent the disease or condition. For example, for the prevention of a stroke, people today take acetylsalicylic acid (aspirin) in an effective amount.
The drug may be accompanied by a suitable form of hyaluronic acid in an effective non-toxic amount. Thus, the taking of the two together will, it is believed, reduce the risk of stroke even more than the individual taking aspirin 25 alone. The form of HA further targets the drug to the areas in need of treatment while the HA binds with the adhesion molecule (for example, ICAM- 1, HARLEC, RHAMM, and CD44) modulating their activity.
The administration may be given, among other methods, intravenously, intra-arterially, intraperitoneally, intrapleurally, - 6 ~ 2~131 130 percutaneously. (intra-cutaneously - into the skin (for example, targeting the epidermis) by topical application of effective amounts and by application to the mucasa by topical application for example, intranasally) rectally (for example, in the form of an enema or by topical application of specific areas in the rectum), 5 and by direct injection.
Where the form of hyaluronic acid is to be administered, varying effective doses may be employed - for example, 10 to lOOOmg/70kg. person with optimal doses tending to range between 50 and 500mg/70kg. person. As there is no toxicity in humans, the hyaluronic acid can obviously be administered in a dose excess (for example 3000mg/70kg. individual) without any adverse effects.
Where the administration is topical (for example, applied to the skin or mucosa), in excess of 5 mg per cm2 (square centimetre) of skin or exposed tissue (including mucosa) of the form of hyaluronic acid, shculd be applied.
With respect to the treatment of pain, preferably a minimum of 15 lOmg per cm2 (lOmg/cm2) of the form of HA should be applied topically.
Thus, effective dosage amounts contain at least about lOmg of the form of hyaluronic acid per 70kg person to in excess of lOOOmg per 70kg person where the administration is non-topical. When an NSAID for example, indomethacin (dissolved in n-methyl glucamine) or other NSAID is administered 20 with greater than 200mg hyaluronic acid for example, sodium hyaluronate per 70kg person with 1 - 2 mg/kg body weight of the person, of the NSAID (in one instance indomethacin and NMG), no major toxic side effects occur such as gastro-intestinal distress, neurological abnormalities, depression, etc., even at elevated amounts of indomethacin (if necessary). If the amount of hyaluronic acid is 25 decreased below that amount, the usual side effects may begin to reoccur. Where administration is topical, the dosage amounts contain at least about 5mg of the form of hyaluronic acid / cm2 of the skin, mucosa or tissue to which the dosage amount is to be applied.
The Drugs accompanying the form of hyaluronic acid are adjusted - 7 - ~3113l~
with the form of treatment to be an effective non-toxic amount thereof.
One form of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, and sub units of hyaluronic acid, preferably hyaluronic acid and salts and thereof 5 suitable for use with Applicant's invention is a fraction suppied by Hyal Pharmaceutical Corporation. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3). The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000 daltons. The fraction also contains water q.s. which is triple distilled and sterile in accordance 10 with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial.
The fraction of hyaluronic acid and/or salts thereof (for example sodium salt) and homologues, analogues, derivatives, complexes, esters, fragments, 15 and sub units of hyaluronic acid, preferably hyaluronic acid and salts thereof may comprise hyaluronic acid and/or salts thereof having the following characteristics:
a purified, substantially pyrogen-free fraction of hyaluronic acid obtained from a natural source having at least one characteristic selected from 20 the group consisting of the following:
i ) a molecular weight within the range of 150,000-225,000;
ii) less than about 1.25% sulphated mucopolysaccharides on a total weight basis;
iii) less than about 0.6% proten on a total weight basis;
i v ) less than about 150 ppm iron on a total weight basis;
v ) less than about 15 ppm lead on a total weight basis;
v i ) less than 0.0025% glucosamine;
vii) less than 0.025% glucuronic acid;
v i i i ) les s than 0.025 % N-acetylglucosamine;
-8- 2-131i3 ix) less than 0.0025% amino acids;
x ) a UV extinction coefficient at 257 nm of less than about 0.275;
x i ) a UV extinction coefficient at 280 nm of less than about 0.25; and xii) a pH within the range of 7.3-7.9.
Preferably the hyaluronic acid is mixed with water and the fraction of hyaluronic acid fraction has a mean average molecular weight within the range of 150,000-225,000. More preferably the fraction of hyaluronic acid comprises at least one characteristic selected from the group consisting of the following characteristic.
i ) less than about 1 % sulphated mucopolysaccharides on a total weight basis;
ii) less than about 0.4% protein on a total weight basis;
iii) less than about 100 ppm iron on a total weight basis;
i v ) less than about 10 ppm lead on a total weight basis;
v ) less than 0.00166% glucosamine;
vi) less than 0.0166% glucuronic acid;
vii) less than 0.0166% N-acetylglucosamine;
viii) less than 0.00166% amino acids;
i x ) a UV extinction coefficient at 257 nm of less than about 0.23;
x ) a UV extinction coefficient at 280 nm of less than 0.19;
5 and xi) a pH within the range of 7.5-7.7 In addition, Applicant has successfully employed sodium hyaluronate produced and suupplied by LifeCoreT M Biodmedical, Inc. having the following specifications:
x ) a UV extinction coefficient at 257 nm of less than about 0.275;
x i ) a UV extinction coefficient at 280 nm of less than about 0.25; and xii) a pH within the range of 7.3-7.9.
Preferably the hyaluronic acid is mixed with water and the fraction of hyaluronic acid fraction has a mean average molecular weight within the range of 150,000-225,000. More preferably the fraction of hyaluronic acid comprises at least one characteristic selected from the group consisting of the following characteristic.
i ) less than about 1 % sulphated mucopolysaccharides on a total weight basis;
ii) less than about 0.4% protein on a total weight basis;
iii) less than about 100 ppm iron on a total weight basis;
i v ) less than about 10 ppm lead on a total weight basis;
v ) less than 0.00166% glucosamine;
vi) less than 0.0166% glucuronic acid;
vii) less than 0.0166% N-acetylglucosamine;
viii) less than 0.00166% amino acids;
i x ) a UV extinction coefficient at 257 nm of less than about 0.23;
x ) a UV extinction coefficient at 280 nm of less than 0.19;
5 and xi) a pH within the range of 7.5-7.7 In addition, Applicant has successfully employed sodium hyaluronate produced and suupplied by LifeCoreT M Biodmedical, Inc. having the following specifications:
9 ~131130 Characteristics Specification A p p e a r a n c e White to cream colored particles Odor No perceptible odor Viscosity Average Molecular Weight < 750,000 Daltons UV/Vis Scan, 190-820nm Matches reference scan OD, 260 nm < 0.25 OD units Hyaluronidase Sensitivity Positive response IR Scan Matches reference pH, 10mg/g solution 6.2-7.8 Water 8% maximum P ro te i n < 0.3 mcg/mg NaHy Acetate < 10.0 mcg/mg NaHy Heavy Metals, maximum ppm As Cd Cr Co Cu Fe Pb Hg Ni 2.0 5.0 5.0 10.0 10.0 25.0 10.0 10.0 5.0 Microbial Bioburden None observed Endotoxin < 0.07EU/mg NaHy Biological Safety Testing Passes Rabbit Ocular Toxicity Test Another form of sodium hyaluronate is sold under the name 20 Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications:
Specification's Test Results Lot No. HG1004 pH 6.12 Condroitin Sulfate not detected Protein 0.05%
Heavy Metals Not more than 20 ppm A r s e n i c Not more than 2 ppm lo ~13113D
Loss on Drying 2.07%
Residue on Ignition 16.69%
Intrinsic Viscosity 12.75 dl/s (XW: 679,000) Nitrogen 3.14%
Assay 104.1%
Microbiological Counts 8 0 / g E. coli Negative Mold and Yeast Not more than 50/g Other forms of hyaluronic acid and/or its salts, and homologues, 10 derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in the prior art. The following references teach hyaluronic acid, sources thereof and processes of the manufacture and recovery thereof.
United States Patent 4,141,973 teaches hyaluronic acid fractions 15 (including sodium salts) having:
"(a) an average molecular weight greater than about 750,000, preferably greater than about 1,200,00 - that is, a limiting viscosity number greater than about 1400 cm3 /g., and preferably greater than about 2000 cm3/g.;
( b ) a protein content of less than 0.5% by weight;
( c ) ultraviolet light absorbance of a 1 % solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wavelength;
(d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
( e ) a molar optical rotation of a 0.1 - 0.2% sodium hyaluronate solution in physiological buffer of less than - 11 x 103 degree cm2/mole (of disaccharide) measured at 220 nanometers;
Specification's Test Results Lot No. HG1004 pH 6.12 Condroitin Sulfate not detected Protein 0.05%
Heavy Metals Not more than 20 ppm A r s e n i c Not more than 2 ppm lo ~13113D
Loss on Drying 2.07%
Residue on Ignition 16.69%
Intrinsic Viscosity 12.75 dl/s (XW: 679,000) Nitrogen 3.14%
Assay 104.1%
Microbiological Counts 8 0 / g E. coli Negative Mold and Yeast Not more than 50/g Other forms of hyaluronic acid and/or its salts, and homologues, 10 derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for example those described in the prior art. The following references teach hyaluronic acid, sources thereof and processes of the manufacture and recovery thereof.
United States Patent 4,141,973 teaches hyaluronic acid fractions 15 (including sodium salts) having:
"(a) an average molecular weight greater than about 750,000, preferably greater than about 1,200,00 - that is, a limiting viscosity number greater than about 1400 cm3 /g., and preferably greater than about 2000 cm3/g.;
( b ) a protein content of less than 0.5% by weight;
( c ) ultraviolet light absorbance of a 1 % solution of sodium hyaluronate of less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280 nanometers wavelength;
(d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
( e ) a molar optical rotation of a 0.1 - 0.2% sodium hyaluronate solution in physiological buffer of less than - 11 x 103 degree cm2/mole (of disaccharide) measured at 220 nanometers;
11 ~1 ~ 1. 1~0 ( f ) no significant cellular infiltration of the vitreous and anterior chamber, no flare in the aqueous humor, no haze or flare in the vitreous and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye when one milliliter of a 1 % solution of sodium hyaluronate dissolved in physiological buffer is implanted in the vitreous replacing approximately one-half the existing liquid vitreous, said HUA being ( g ) sterile and pyrogen free and ( h ) non-antigenic. "
Canadian Letters Patent 1,205,031 (which refers to United States Patent 4,141,937 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to 730,000 and discusses processes of their manufacture.
Where high molecular weight hyaluronic acid (or salts or other forms thereof) is used, it must be diluted to permit administration and ensure no intramuscular coagulation.
According to one aspect of the invention, a dosage amount of a pharmaceutical composition is provided for the modulation of cellular activity of 20 tissue and cells expressing an adhesion molecule (for example, ICAM-l, HARLEC, CD44, and RHAMM) of a human, the dosage amount comprising a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a 25 form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues - 12- ~3113D
and/or cells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
The result of the treatment by the dosage amount is that tissue and/or cell modulation is enhanced in the person suffering the disease or condition. The result of the administration of the form of hyaluronic acid (HA) is the inhibition of cellular adhesion and/or modulation of cellular activity. The HA
binds to the HA receptors of the adhesion molecule.
The dosage amount of the pharmaceutical composition may also comprise an effective non-toxic amount of a medicine (drug) or therapeutic agentfor the treatment of the disease and/or condition accompanying the form of hyaluronic acid. The drug, therefore, enhances the modulation of the form of theHA activity. The form of HA further targets the drug to the adhesion molecule (for example, ICAM-1, HARLEC, RHAMM, and CD44.
Thus, according to another aspect of the invention, a dosage amount of a pharmaceuitcal composition may comprise:
i ) a medicinal and/or therapeutic agent in a non-toxic therapeutically effective amount to treat a disease or condition;
i i ) a non-toxic therapeutically effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons, and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or -13 ~113a combinations thereof) to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body, and iii) a pharmaceutically tolerable carrier (for example, sterile water);
wherein component (ii) is in such form that when the dosage amount of the pharmaceutical composition is applied, component (ii) isimmediately available to transport component (i) in the body or into the skin asthe case may be and is available when transported to modulate the cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM- 1, HARLEC, CD44 and RHAMM) of a human by for example, binding with the receptor for the form of hyaluronic acid Suitable medicines (drugs) and therapeutic agents may comprise for example, a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e. g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenT M contraceptive cream, and anionic surfactants (e.g. cetyl pyridiniumchloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolT M ) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixT M ), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), alpha-and-B-interferon, and the like.
Dosage amounts of the pharmaceutical compositions may be - 14 - ~l~ J 13 D
accumulated in containers to supply multiple dosage amounts from which an individual dosage amount may be taken.
As many changes can be made to examples of the invention without departing from the scope of the invention, it is intended that all material 5 contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Canadian Letters Patent 1,205,031 (which refers to United States Patent 4,141,937 as prior art) refers to hyaluronic acid fractions having average molecular weights of from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to 730,000 and discusses processes of their manufacture.
Where high molecular weight hyaluronic acid (or salts or other forms thereof) is used, it must be diluted to permit administration and ensure no intramuscular coagulation.
According to one aspect of the invention, a dosage amount of a pharmaceutical composition is provided for the modulation of cellular activity of 20 tissue and cells expressing an adhesion molecule (for example, ICAM-l, HARLEC, CD44, and RHAMM) of a human, the dosage amount comprising a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a 25 form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues - 12- ~3113D
and/or cells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
The result of the treatment by the dosage amount is that tissue and/or cell modulation is enhanced in the person suffering the disease or condition. The result of the administration of the form of hyaluronic acid (HA) is the inhibition of cellular adhesion and/or modulation of cellular activity. The HA
binds to the HA receptors of the adhesion molecule.
The dosage amount of the pharmaceutical composition may also comprise an effective non-toxic amount of a medicine (drug) or therapeutic agentfor the treatment of the disease and/or condition accompanying the form of hyaluronic acid. The drug, therefore, enhances the modulation of the form of theHA activity. The form of HA further targets the drug to the adhesion molecule (for example, ICAM-1, HARLEC, RHAMM, and CD44.
Thus, according to another aspect of the invention, a dosage amount of a pharmaceuitcal composition may comprise:
i ) a medicinal and/or therapeutic agent in a non-toxic therapeutically effective amount to treat a disease or condition;
i i ) a non-toxic therapeutically effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons, and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or -13 ~113a combinations thereof) to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body, and iii) a pharmaceutically tolerable carrier (for example, sterile water);
wherein component (ii) is in such form that when the dosage amount of the pharmaceutical composition is applied, component (ii) isimmediately available to transport component (i) in the body or into the skin asthe case may be and is available when transported to modulate the cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM- 1, HARLEC, CD44 and RHAMM) of a human by for example, binding with the receptor for the form of hyaluronic acid Suitable medicines (drugs) and therapeutic agents may comprise for example, a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e. g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenT M contraceptive cream, and anionic surfactants (e.g. cetyl pyridiniumchloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolT M ) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixT M ), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), alpha-and-B-interferon, and the like.
Dosage amounts of the pharmaceutical compositions may be - 14 - ~l~ J 13 D
accumulated in containers to supply multiple dosage amounts from which an individual dosage amount may be taken.
As many changes can be made to examples of the invention without departing from the scope of the invention, it is intended that all material 5 contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims (13)
1. According to one aspect of the invention, a method for the modulation of cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM-1, HARLEC, CD44, and RHAMM) of a human is provided the method comprising the administration of a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissuesand/or cells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
2. The method of Claim 1 further comprising a therapeutically effective non-toxic amount of a medicine (drug) or therapeutic agent for the treatment of the disease and for condition.
3. The method of Claim 2 wherein the medicine (drug) and/or therapeutic agent may comprise an agent selected from a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenTM contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolTM) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixTM), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), or alpha-and-B-interferon.
4, Use of a form of hyaluronic acid, for example, hyaluronic acid, a salt thereof (for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons), molecular fractions thereof [for example, those disclosed in Canadian Letters Patent 1205031 (to FIDIA) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000, daltons or other fractions] homologues, analogues, derivatives, complexes, esters, fragments and/or subunits of hyaluronic acid and/or combinations thereof is provided to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body.
5. The use of Claim 4 further comprising a drug in an effective non-toxic amount.
6. The use of Claim 5 wherein the drugs may comprise an agent selected from a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenTM contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolTM) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixTM), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), or alpha-and-B-interferon.
7. A method of preventing a disease and/or condition, the method comprising administering an effective non-toxic amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons] molecular weight fractions of a form of sodium hyaluronate [for example, fractions disclosed in Canadian Letters Patent 125031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons or other fractions], homologues, analogues, derivatives, complexes, esters, fragments and/or subunits of hyaluronic acid and/or combinations thereof to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body to thereby prevent a disease or condition.
8. The method of Claim 7 further comprising drugs to assist to prevent a disease or condition administered with the form of hyaluronic acid (HA).
9. A dosage amount of a pharmaceutical composition is provided for the modulation of cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM-1, HARLEC, CD44, and RHAMM) of a human, the dosage amount comprising a non-toxic effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in the human body, in a pharmaceutical carrier tolerable by the human (for example, sterile water).
The result of the treatment by the dosage amount is that tissue and/or cell modulation is enhanced in the person suffering the disease or condition. The result of the administration of the form of hyaluronic acid (HA) is the inhibition of cellular adhesion and/or modulation of cellular activity. The HA
binds to the HA receptors of the adhesion molecule.
The result of the treatment by the dosage amount is that tissue and/or cell modulation is enhanced in the person suffering the disease or condition. The result of the administration of the form of hyaluronic acid (HA) is the inhibition of cellular adhesion and/or modulation of cellular activity. The HA
binds to the HA receptors of the adhesion molecule.
10. The dosage amount of Claim 9 further comprising an effective non-toxic amount of a medicine (drug) or therapeutic agent for the treatment of the disease and for condition accompanying the form of hyaluronic acid.
11. A dosage amount of a pharmaceuitcal composition comprising:
i) a medicinal and/or therapeutic agent in a non-toxic therapeutically effective amount to treat a disease or condition;
ii) a non-toxic therapeutically effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons, and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in he human body, and iii) a pharmaceutically tolerable carrier (for example, sterile water);
wherein component (ii) is in such form that when the dosage amount of the pharmaceutical composition is applied, component (ii) is immediately available to transport component (i) in the body or into the skin as the case may be and is available when trasported to modulate the cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM-1, HARLEC, CD44 and RHAMM) of a human by for example, binding with the receptor for the form of hyaluronic acid
i) a medicinal and/or therapeutic agent in a non-toxic therapeutically effective amount to treat a disease or condition;
ii) a non-toxic therapeutically effective amount of a form of hyaluronic acid (for example, hyaluronic acid, a salt thereof, [for example, sodium hyaluronate having a molecular weight less than 750,000 daltons, for example, 300,000 daltons], molecular weight fractions of a form of sodium hyaluronate (for example, fractions disclosed in Canadian Letters Patent 1205031 (to Fidia) such as those from 50,000-100,000 daltons, 250,000-350,000 daltons, and 500,000-730,000 daltons, or other fractions, homologues, analogues, derivatives, complexes, esters, fragments and/or sub units of hyaluronic acid and/or combinations thereof) to a human to modulate cellular activity of tissues and/or cells expressing an adhesion molecule in he human body, and iii) a pharmaceutically tolerable carrier (for example, sterile water);
wherein component (ii) is in such form that when the dosage amount of the pharmaceutical composition is applied, component (ii) is immediately available to transport component (i) in the body or into the skin as the case may be and is available when trasported to modulate the cellular activity of tissue and cells expressing an adhesion molecule (for example, ICAM-1, HARLEC, CD44 and RHAMM) of a human by for example, binding with the receptor for the form of hyaluronic acid
12. The dosage amount of Claim 11 wherein the suitable medicines (drugs) and therapeutic agents may comprise for example, a free radical scavenger (for example ascorbic acid (Vitamin C)), an anti-cancer agent, chemotherapeutic agent, anti-viral agents for example a nonionic surfactant, e.g.
nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenTM
contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolTM) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixTM), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), alpha-and-B-interferon, and the like.
nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in DelfenTM
contraceptive cream, and anionic surfactants (e.g. cetyl pyridinium chloride) and cationic surfactants (e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin, naproxen and (+/-) tromethamine salt of ketorolac (sold under the trademark ToadolTM) and steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents (for example for administration rectally in an enema), analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia (for example diabetes and Berger's disease), anti-body monoclonal agent, minoxidil for topical application for hair growth, diuretics (for example furosemide (sold under the trademark LasixTM), immunosuppressants (for example cyclosporins), lymphokynes (such as interleukin - 2 and the like), alpha-and-B-interferon, and the like.
13. A container comprising multiple dosage amounts of Claims 9, 10, 11, or 12 from which individual dosage amounts may be taken.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002131130A CA2131130A1 (en) | 1994-08-30 | 1994-08-30 | Modulation of cellular activity |
| IL11491495A IL114914A0 (en) | 1994-08-30 | 1995-08-11 | Modulation of cellular activity |
| AU31595/95A AU3159595A (en) | 1994-08-30 | 1995-08-11 | Hyaluronic acid and derivatives for modulation of cellular activity |
| KR1019970701164A KR970705401A (en) | 1994-08-30 | 1995-08-11 | HYALURONIC ACID AND DERIVATIVES FOR MODULATION OF CELLULAR ACTIVITY FOR ADJUSTING CELL ACTIVITY |
| EP95927605A EP0778776A1 (en) | 1994-08-30 | 1995-08-11 | Hyaluronic acid and derivatives for modulation of cellular activity |
| JP8508371A JPH10504828A (en) | 1994-08-30 | 1995-08-11 | Hyaluronic acid and its derivatives for regulating cell activity |
| PCT/CA1995/000477 WO1996006622A1 (en) | 1991-07-03 | 1995-08-11 | Hyaluronic acid and derivatives for modulation of cellular activity |
| HU9701507A HUT76846A (en) | 1994-08-30 | 1995-08-11 | Hyaluronic acid and derivatives for modulation of cellular activity |
| APAP/P/1995/000756A AP618A (en) | 1994-08-30 | 1995-08-14 | Modulation of cellular activity by administering a form of hyaluronic acid. |
| CN95116995A CN1130532A (en) | 1994-08-30 | 1995-08-29 | Modulation of cellular activity |
| ZA957223A ZA957223B (en) | 1994-08-30 | 1995-08-29 | Modulation of cellular activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002131130A CA2131130A1 (en) | 1994-08-30 | 1994-08-30 | Modulation of cellular activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2131130A1 true CA2131130A1 (en) | 1996-03-01 |
Family
ID=4154258
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002131130A Abandoned CA2131130A1 (en) | 1991-07-03 | 1994-08-30 | Modulation of cellular activity |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2131130A1 (en) |
| ZA (1) | ZA957223B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070256A1 (en) * | 2002-02-15 | 2003-08-28 | Research Development Foundation | Hyaluronic acid mediated adenoviral transduction |
-
1994
- 1994-08-30 CA CA002131130A patent/CA2131130A1/en not_active Abandoned
-
1995
- 1995-08-29 ZA ZA957223A patent/ZA957223B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070256A1 (en) * | 2002-02-15 | 2003-08-28 | Research Development Foundation | Hyaluronic acid mediated adenoviral transduction |
| US7144870B2 (en) | 2002-02-15 | 2006-12-05 | Research Development Foundation | Hyaluronic acid mediated adenoviral transduction |
| CN1309392C (en) * | 2002-02-15 | 2007-04-11 | 研究发展基金会 | Hyaluronic acid mediated adenoviral transduction |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA957223B (en) | 1996-04-01 |
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