AU596838B2 - Creation of Inventions and Patents with Artificial Intelligence

AU596838B2 – Remote administration of hyaluronic acid to mammals
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AU596838B2 – Remote administration of hyaluronic acid to mammals
– Google Patents
Remote administration of hyaluronic acid to mammals

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Publication number
AU596838B2

AU596838B2
AU71782/87A
AU7178287A
AU596838B2
AU 596838 B2
AU596838 B2
AU 596838B2
AU 71782/87 A
AU71782/87 A
AU 71782/87A
AU 7178287 A
AU7178287 A
AU 7178287A
AU 596838 B2
AU596838 B2
AU 596838B2
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AU
Australia
Prior art keywords
hyaluronic acid
treatment
injection
horse
tissue
Prior art date
1986-04-28
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Application number
AU71782/87A
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AU7178287A
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Inventor
Karen K. Brown
Nathan D. Greene
John O. Mozier
Richard H. Schultz
Terry S. Wollen
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Bayer Corp

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Mobay Corp
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1986-04-28
Filing date
1987-04-15
Publication date
1990-05-17

1987-04-15
Application filed by Mobay Corp
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Mobay Corp

1987-10-29
Publication of AU7178287A
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patent/AU7178287A/en

1990-05-17
Application granted
granted
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1990-05-17
Publication of AU596838B2
publication
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patent/AU596838B2/en

2007-04-15
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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

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

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P17/00—Drugs for dermatological disorders

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A61P25/04—Centrally acting analgesics, e.g. opioids

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present disclosure is concerned with the discovery that hyaluronic acid, an agent well known to reduce the sequelae of trauma in mammalian joint tissue when applied directly to the traumatized tissue, will be carried to such traumatized tissue by the mammal’s natural processes if applied at a site remote from the traumatized tissue. Thus, hyaluronic acid, in any therapeutically acceptable form, can be administered by the typical remote routes including intravenous, intramuscular, subcutaneous and topical. This makes the utilization of hyaluronic acid much more convenient and attractive. For instance the treatment of arthritis in horse or human joints with hyaluronic acid no longer requires more difficult intra articular injections.

Description

r r’ i 4075-P7 HC:MV 0405T.13
AUSTRALIA
PATENTS ACT 1952 COMPLETE SPECIFICATI5 6 8 8
(ORIGINAL)
FOR OFFICE USE 7 7 2-/-7 Application Number: Lodged: Complete Specification Lodged: Accepted: Published: This docutnent C(cot7aj.ns th”e anleldments made under Section 49ind is corlelt 1,o1 i~rin ing.
‘,Priority: ,Related Art: o t TO BE COMPLETED BY APPLICANT Name of Applicant: t Address of Applicant: Actual Inventor: Address for Service: Address for Service: MOBAY CORPORATION Mobay Road, Pittsburgh, PA 15205, U.S.A.
RICHARD H. SCHULTZ, TERRY S.
WOLLEN, NATHAN D. GREENE, KAREN K. BROWN, JOHN O. MOZIER ARTHUR S. CAV7 CO.
Patent Trade Mark Attorneys Goldfields House 1 Alfred Street SYDNEY N.SW. 2000
AUSTRALIA
aO Complete Specification for the invention entitlerC REMOTE ADMINISTRATION OF HYALURONIC ACID TO MMMMALS.
The following statement is a full description of this invention including the best method of performing it known to me:- 1 ASC 49 14- .MIo*- r f “-s~U~NICC^Cli a -I Mo-2817 REMOTE ADMINISTRATION OF HYALURONIC ACID TO MAMIALS FIELD OF THE INVENTION The present invention is concerned with the discovery that a known therapeutic agent, hyaluroric acid, can be effectively administered to mammals by techniques whi equire the mammal’s internal bodily processes to transport this high molecular weight agent to thr site of action.
BACKGROUND OF THE INVENTION Hyaluronic acid is a well known mucopolysacchar’ide which is found in the joint tissue and vitreous humor of the eyes of mammals. It has been extracted from rooster combs and human umbilical cords and bacterial cultures such as those of hemolytic group A and C streptococci for various therapeutic purposes.
The initial therapeutic usc of this material was as a replacement for the liquid vitreous of the human eye to aid in ophthalmic surgery, especialli’ in the treatment of retinal detachment. It has also found utility for S 20 the relief of trauma or irritation ir joint tissue of mammals including humans by injection into the synovial fluid of the joint. It has been proposed that it be o used both as a primary medicant and as an auxiliary with other joint medicines. An extensive discussion of its various utilities is found in U.S. Patent No. 4,141,973 to Balazs. The use of hvaluronic acid alone and with 0*<00 cortisone in various animal joints, especially horses, is discussed the "Effect of Intra--rticular Injection Hyaluronic Acid on Clinical Symptoms 30 Osteoarthritis and Granulation Tissue Formation" by Rydell et al. appearing at pager 25 to 32 0 69 o Mo-2817 2 October, 1971 (Number 80) issue Orthopaedics Related Research. The use hyaluronic acid human joints reported "Preliminary Assessment Na Hyaluronate into Human Arthritic Joints" Peyron al pages 731 736 October 1974 (Volume 22, Number 8) Pathologie Biologie. Finally, reducing fibrotic wound reactions "Decreased Reaction After Installment Acid" 307 311 Volume 41 Acta Orthop.Scandinav. The intra-articular horse has been commercially prrmoted connection with Pharmacia's Hylartil R Hylartin V product Sterivet's Synacid product. However, commercial attractiveness limited need administer these products injection affected joint. A related material, a polysulfated glycosaminoglycdn, 9 9a 99° recntly introduced U.S. market Luitpold :00 (R) Sooo Pharmaceuticals under tradename Adequan (also known Europe as Arteparon R for treatment arthritic horses. Initially recommended route administration was 250 mg each week for five veeks, A letter 446 447 April, 1984 Veterinary Medicine suggests that this matrial can V, be administered intramuscularly approximately double S dosage four day interval weeks. Polysulfated glycoaminoglycans have also stimulate biosynthesis synovial membranes rabbit knee 0523E 3 thus suggesting although mode action may different from same conditions might beneficially effected. Interestingly report, "Influences Sulfated Glycosaminoglycans Biosynthesis Rabbit Knee Synovial Membrane", Nishikawa 146 153 July, 1985 240) Arch. Biochem. Biophys. indicates itself no such stimulatory effect. This agent effective if either humans or subcutaneously rats. former effect noted "Vergleich von Glykosaminoglykanpolysulfat (Arteparon) und physiologischer Kochsalzloesung bei Arthrosen grosser Gelenke.Ergebnisse einer multizentrischen Doppelblindstudie" Siegmeth 223 228 July>r I >\ie-r resu\t &r evumc of traumatized or irritated mammalian tissue, particularly joint tissue.
SUMMARY OF THE INVENTION A process for reducing the sequela of the trauma in irritated or inflamed mammalian tissue by the remote administration of hyaluronic acid or a pharmacologically acceptable salt thereof has been discovered. (Hereinafter for convenience the term hyaluronic acid is used to denote both the free acid and the pharmacologically acceptable salts thereof interchangeably except where otherwise explicitly indicated).
The hyaluronic acid is introduced to the body of the mammal at other than the site of the traumatized tissue and is effectively transported to the site of action by the body’s S internal processes. This allows the use of such convenient routes of administration as intramuscular, intravenous, 0 C0 o subcutaneous, and topical. Two particularly preferred routes S of administration are intramuscular injection and topical application in a recognized transdermal carrier and a Q o particularly amendable condition for such treatment is irritated or inflamed joint tissue.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a set of plots of the change in carpal joint 0 circumference versus the time after treatment with hyaluronic acid for treated and control horses with Freund’s Complete S Adjuvant induced trauma in the carpal joint.
Ss o Figure 2 is a set of plots of the change in range of 06 motion versus the time after treatment for the same horses as in Vigure 1.
T0523E 0523E 6 Figure 3 is a set of plots of the change in range on motion normalized to the day of treatment versus the time after treatment for the same horses as in Figure 1.
Figure 4 is the i;ame set of plots as in Figure 3 but with all ordinate values ‘rbitrarily increased by 23.7% to set the lowest point at 0%.
Figure 5 is a set of plots of lameness index versus time after ‘reatment for the same horses as in Figure 1.
Figure 6 is a set of plots of the per cent improvement in stride versus time after treatment for the same horses as in Figure 1.
DETAILED DESCRIPTION OF THE INVENTION The trauma in irritated or inflamed mammalian tissue is reduced by applying hyaluronic acid by any of the acceptec routes of administation except direct application to the affected tissue. A particularly interesting embodiment S involves the treatment of joint tissue. The direct application Sof hyaluronic acid involves intra-articular injection which is Sa procedure requiring considerable care and skill in the larger joints of larger mammals such as the leg joints of horses. The treatment of smaller mammals such as dogs and cats and the smaller joints of larger mammals such as human finger joints requires correspondingly greater care and skill. Treatment by remote administration such as intramuscular, intravenous or subcutaneous injection or topical application in a transdermal carrier in such cases is much more convenient and attractive.
However, the fact that the internal transport systems of the So, mammalian body are effective in conveying hyaluronic acid to the affected site makes it possible to treat other traumatized tissue by remote application as well, S a 0523E -7- Thus, remote administration can be used to treat the other conditions for which hyaluronic acid has found utility such as the post surgical adhesion associated with incisions and tendon repair reported on in the Rydell et al article appearing at pages 25 to 32 of the October 1971 issue of Clinical Orthopedics and Related Research.
The hyaluronic acid useful in the treatment of irritated or inflamed tissue by remote application may be of any type already recognized as useful for such purposes. It may be extracted from animal tissue such as rooster combs or umbilical cords or from bacterial cultures such as those of hemolytic group A or C streptococci. It should be pure by enough to avoid provoking an adverse or toxic reaction in the mammal being treated. This implies that it is free of pyrogens and has a sufficiently low level of proteins and nucleic acids that S no substantial immune reaction is provoked. It is preferably of high molecular weight and is also preferably of low o* viscosity for the injection routes. The polymer may be in its free acid form or in any pharmacologically acceptable salt form.
The preferred source of hyaluronic acid is a culture of an appropriate microorganism. The use of the culturing and har esting techniques described in European Published Patent Application No. 144,019 are particularly valuable in obtaining material with desirable purity and molecular weight. Among the 7o organisms to which these techniques can be applied the Group A o o and Group C streptococci are preferred with the Group C being S especially preferred and the Streptococcus e ui being most j preferred. Further preferred is the hyaluronic acid obtained according to the teachings of copending U.S. Patent Application Serial No. 816,548 filed January 6, 1986.
S0523 0523E 1 -8- Both the protein and amino acid content, and the nucleic acid content of the hyaluronic acid should be carefully controlled because both are known to display antigenic activity in mammals. The content of both are conveniently monitored and evaluated by UV absorbance with the former correlated to the optical density a.r 280 nanometers and the latter to the optical density at 257 nanometers. It is preferred that the content of the former be less than about 1.25, especially less than about 0.1, mg/ml and that the content of the latter be less than about 0.06, especially less than about 0.005, mg/ml. In this regard the absorbance at 280 nanometers does not distinguish between amino acids and proteins. However, while amino acids alone are non-antigenic, they readily complex with hyaluronic acid and the complex may readily provoke an immune response in mammals. Therefore in the context of the present technology it is desirable to control the content of both and thus it is appropriate to specify a maximum content for the combination of both which is correlated with a particular IUV absorbance. In an especially preferred hyaluronic acid the total amino acid content as measured by the orthophthalaldehyde fluovesence technique (which inherently involves the S 25 hydrolysis of any protein present back to its constituent amino acids) is less than about 0.4 mg/ml.
and the nucleic acid content is less than about 0.06 mg/ml as measured by the ethidium bromide fluorescence technique, 30 The hyaluronic acid can be utilized in its free acid form or in any pharmacologically acceptable salt form. One of the most convenient forms is as the sodium salt because this polymer is typically purified by successive precipitations in ethanol or other organic Mo- 2 8 17 9 9 solvents and dissolutions in water and the sodium salt is particularly amenable to such procedures. In fact, all the limitations on purity, viscosity and molecular weight discussed herein were developed on the sodium salt as were the specific application data discussed hereinafter. However, the remote application development is equally applicable to other forms such as the free acid or potassium salt. For convenience the discussed herein includes all these forms within the term hyaluronic acid.
The hyaluronic acid should have a high average molecular weight. Although forrs of this material with average molecular weights of 55,000 or less are known the preferred hyaluronic acid has an averace molecular weight of at least 5 x 10 00 0 S determined by FPLC (fast protein liquid chromatography) in o o o accordance with the technique disclosed in copending U.S.
o Patent Application S/N 816,548 filed January 6, 1986. Average 6 molecular weights in excess of about 1.0 x 10 preferably 6 6 S 1.2 x 10 and especially in excess of about 1.8 x 10 are r Sparticularly preferred. it is farther preferred that the hyaluronic acid display a fairly narrow molecular weight distribution and a distribution with a cingle gel permeation peak is particularly preferred. A single symmetrical FPLC peak with 98% of the molecules having a weight between about 1.2 x o 6 6 10 and 4.0 x 10 is especially preferred.
The hyaluronic acid may have either a high or a low S viscosity depending on what is convenient for the route of treatment desired- The higher viscosities are convenient for topical applications while the lower viscosities are convenient for the injection route of administration, i.e. intra-muscular, intravenous or subcutaneous. The higher molecular weight hyaluronic 0523E 10 acid may advantageously have viscosities between about 900 and 5000 centistokes per second at 37 0 C for topical applications and advautageously have viscosities less than about 500, preferably less than 150 c/s at 37 0 C for other routes of administration. In both cases the viscosity is conveniently measured as a 1 wt. aqueous solution of the sodium salt in a Cannon-Manning Semi-Micro Viscometer according to the procedures in ASTM D 445 and D 2515. The low viscosity material greatly facilitates the injection routes of administration by allowing for instance the use of reasonably concentrated aqueous sodium hyaluronate solution in practical size doses. Thus, a 1% aqueous solution of sodium hyaluronate can be readily utilized for injection doses of about S milliliters which contain about 100 milligrams of active ingredient if its viscosity is less than about 200 c/s at 37 0
C.
The treatment of irritated or inflamed mammalian tissue by Sremote administration requires a dose or total dose regimen VI effective to reduce or alleviate the trauma. It is preferred to administer at least about 0.02 milligrams of hyaluronic acid per pound of body weight of the mammal being treated which is equivalent to about 0.044 milligrams per kilogram. It is particularly preferred to utilize at least about 0.04 and S especially 0.08 milligrams per pound of body weight. In the case of topical application it is particularly desirable to use in excess of about 0.10, especially about 0.15, milligrams per pound of body weight. In as much as hyaluronic acid is a naturally occurring substance in mammals it is believed that there is no inherent upper limit to the tolerable dose.
However, as in all medicinal treatments, i- is prudent to use no more than is necessary to achieve the desired effect.
0523E ii I1 11 Furthermore, any impurities which are at a low enough level to be well tolerated at effective dosages may provoke adverse reactions at unwarrentedly high dosages.
The topical treatment should be made by application of the hyaluronic acid combined with a compatible transdermal carrier. Any recognized carrier such as methyl salicylate, sodium salicylate, benzyl alcohol, oleic acid, 10% propylene glycol, 1% sodium glycolate, 1% polyoxyethylene-10-cetyl ether, 0.1% sodium EDTA, 1% sodium dodecyl sulfate, or dimethyl sulfoxide (DMSO) is suitable with DMSO being particularly preferred. A convenient application formulation is a mixture of a less than about 3 weight percent aqueous solution of hyaluronic acid, particularly as sodium hyaluronate, with an Seffective amount of transdermal carrier. A preferred S formulation involves an aqueous between about 0.5 and weight percent hyaluronfte solution and up to about 30 volume percent of t’:ansdermal carrier. The jyaluronate solution and the total formulation both conveniently display a viscosity in excess of about 1000 c/s at 3l C.
The present treatment has been found to be particularly effective in the treatment of joint distress in large mammals including that caused by arthritic conditions. Especially S preferred applications involve the treatment of horses and man by intramuscular injection and topical administration in a transdermal carrier. A particularly effective treatment for S joint pain in the leg joints, particularly the carpal and tibiotarsal (or hock) joints, of horses is an intramuscular injection preferably in the neck muscle. A particularly effective treatment for musculoskeletai pain in man is topical application in a transdermal carrier such as dimethyl sulfoxide (DMSO). The 0523E i 12 application may be in the vicinity of the affected joint tissue or it may be considerably more remote.
The remote application techniques of the present invention can also be utilized to alleviate any other condition against which hyaluronic acid is recognized as effective. Among these are the reduction or prevention of adhesions at the aite of surgical intrusion, especially in the case of surgery involving tendons.
The remote application technique of the present invention are of particular interest with regard to those mammals which are among the commonly recognized companions to man. The amelioration of pain or discomfort in these companion animals is of the greatest interest and is the most practical among all 0 6 %o treatable mammals. Of particular interest in this group are S the cat, dog and horse.
t The invention is further illustrated but is not intended o to be limited by the following examples.
0 0 e0 0 6 0 *0 0 0523E 13 EXAMPLE 1 An investigation of the intramuscular treatment of horses.
A study involving eight mixed breed female and gelding horses was undertaken to determine if the intramuscular injection of sodium hyaluronate could alleviate the symptoms induced by the intra-articular injection of Freund’s Complete Adjuvant into the intercarpal joint. This is a common and well accepted model for the study of joint distress, particularly arthritic conditions, in horses. The study established that three intramuscular injections of 0.08 milligrams per pound of horse weight given in the neck muscle 5, 9 and 13 days after inducement of joint distress with a 0.7 milliliter injection of the Adjuvant was effective.
The eight horses were initially acclimated to the housing facilities and testing apparatus for several days and then evaluated against the test criteria of joint circumference, range of motion, stride and laminess to provide a base score.
The following day all eight horses were given a 0.7 milliliter injection of Freund’s Complete Adjuvant in the left intercarpal joint. The horses displayed soreness in the left front leg over the next four days. On the fourth day after the intra-articular injection of the irritant the horses were S re-rated against the same four criteria. A total score was developed for each horse consisting of the sum of the differences in each parameter except stride between the two 1 measurements. These scores were then used to assign four i horses to a control group and tour to a treatment group by “assigning the horse with the highest scores to the oLh.er group, the horses with the next two highest scores to the first group, the two 0523E I i 14horses with the next score to the second group and the last horse t-o the first group. The first group was designated the control group by an arbitrary toss of a coin. The table of measurements was as follows with measurement days arbitrarily designated -6 and -1: S t Mo-281
I
p 7 o oO~ 00 *00 I: 1 000 4 00 0 4 C- C C CC, e C C C C C 0 C H dorse No.
1 2 3 4 6 7 8 Ranking 1 2 3 4 6 7 8 Circumference Range or Motion Lameness Stride -6 -1 Dirr. -6 -1 Dirff. -6 -1 Dirr. Total -6 -1 Diff. Total 31.9 29.4 29.3 30.0 29.3 31.5 29.5 31.0 36.2 34.4 33.5 35.5 33.4 36.2 36.0 34.5 Horse No.
3 6 5 4 7 2 8 1 4.3 5.0 3.7 5.5 3.6 4.7 5.5 3.5 155° 150″ 1600 195″ 150″ 1900 150° 150″ 138.7 113.7 112.6 110.5 10: .0 105.0 98.5 98.3 90g 0 950 0 130″ 0 1000 0 105″ 0 105” 0 950 0 900 0 Group 1 3 4 7 1 Mean Score 4 5 5 5 4 4 5 5 98.3 105.0 138.7 110.5 112.6 113.7 105.5 98.5 157.1 161.5 151.1 160.4 163.1 161.3 145.4 157.9 138.5 76.1 78.5 0 126.7 145.7 100.9 114.7 18.2 85.4 82.8 160.4 36.4 15.6 44.5 40.2 116.5 190.4 221.5 270.9 149.0 134.2 150.0 138.7 Control 138.7 110.5 105.5 98.3 113.25 Group 11 6 5 2 8 Mean Score Treatment 113.7 112.6 105.0 98.5 107.45 r 16 On the next day (day 0) each of the horses was given an injection in the neck muscle of between 7.5 and milliliters, depending on body weight. Each horse received an injection to the nearest 0.5 ml of 0.008 milliliters per pound of weight. The injection for the treatment horses consisted of a sterile 1.19 wt. aqueous solution of sodium hyaluronate having a FPLC determined average molecular weight of 1.88 x 106, a nucleic acid content of less than 0.003 mg/ml by ethidium bromide fluoresence, a total amino acid content by ortnophthalaldehyde fluorescence of less than 0.005 mg/ml and a 37 0 C viscosity of 147 c/s while the injection for the control horses consisted of a sterile phosphate buffered saline solution. The weight of each horse and the dosage given to it at this time and four and eight days subsequently was as follows: HORSE WEIGHT IN LBS DOSE IN ML 1 1190 °o 2 1015 g 0.20 3 985 4 1215 0 a ,o 5 1030 6 121.0 7 945 8 1180 The injection site was palpated and the body temperature 4 was taken daily for three days after the first injection and at the time of the second and third injections and 04 finally four days after the third injection. The IM treatment produced no deleterious effect. All temperatures remained normal and there was no clinically significant injection site reaction (the Freund’s Complete Adjuvant is a “known pyrogen” so temperature normality was judged by the fact that the treatment Mo-2817 17injections did not cause any further temperature elevation and did not appear to interfere with the drop in temperature from the peak induced by the traumatizing injection).
Each horse was evaluated against the criteria of joint circumference, range of motion, stride length and observed lameness seven, fourteen, twenty-one, twenty-eight, thirty-five and forty-two days after the first injection. These were the same parameters as had been used to classify the horses into the treatment and control groups and were defined as follows: Joint Evaluation Procedure 1. Joint Circumference Joint circumference was measured while at the stall before exercise. It was measured at a point directly over the accessory carpal bone. It was measured with a cloth tape and recorded in O s t Scentimeters.
o 2. Range of Motion °o 20 Range of Motion was measured at the stall. It was S the difference between the angle of the affected leg o at rest and the flexed angle. All three values were recorded. A goniometer was used to determine the angles.
a. Leg at rest: With the. horse in a standing position, the goniometer measured the angle of oa the carpus.
b. Flexed angle: The affected joint was flexed while the leg was raised from the ground. The goniometer measured the angle at the point where the horse reacted to the flexion by flinching, .shying or pulling back.
Mo-2817 1~1~ 18 3. Stride Length Stride length was measured before being placed on the walker. A long paper roll (20 feet) was used to record the distance between toe marks. Prior to walking across the paper, the toe of the affected leg was sloshed with water or mineral oil. Two steps were recorded and the distance between the toe mark from the affected leg was measured in centimeters. The horse was walked across the paper three times. An average of the three measurements was used for the final value.
4. Observed Lameness The horse was placed on the mechanical walker and walked at 6 m.p.h. for five minutes. The score is determined while on the walker. The direction of the mechanical walker was such’ that the affected leg .was to the inside.
0 No Lameness 1 Difficult to observe; not consistently apparent 20 regardless of circumstances weight-carrying, circling, inclines, hard surface, etc.).
2 Difficult to observe at a walk or trotting a straight line; consistently apparent under certain circumstances weight-carrying *o circling, inclines, hard surface, etc.).
3 Consistently observable at a trot under all circumstances.
P%.o 4 Obvious lameness; markeu nodding, hitching or shortened stride.
Minimal weight-bearing in motion and/or at rest; o’r inability to move.
If a horse was very reluctant to move, and placement on the mechanical walker was not advised, a score of Mo-2817 1 -ii~i- 19 was recorded and the horse was returned to the stall.
An analysis of these parameters clearly demonstrated the beneficial result of the intramuscular injections of the hyaluronic acid in relieving the trauma induced by the Freund’s Complete Adjuvant. The treatment horses displayed clearly superior performance to the control horses in every parameter but joint circumference for which the results were not as conclusive. This is in accord with other studies on the relief of trauma in horse joints wherein joint circumference was found not to be a particularly 0 sensitive measurement parameter. The results are S” tabulated in the following table in which the “day” is 15 the days before or after the first injection: 0 0 0 a s 0 0i Mo-2817 -ii o 0o 0 Ir 00 0 0 0D lint Ilo 0 Trea tmenL co
I-.
-Se 10.
2 5 6 Parameter (In. Cni) Control 1 -6 29.4 29.8 31.5 29.8 30.0 31.9 30.5 150″ 150″ 150″ 140″ 160″ 145″ 155″ 150″ c -1 34.5 33.4 36.2 Range! or Motion Treatment Z 6 3 Control
I
33.5 35.5 36.2 36.0 60″ 550 15″ 350 30″ 45″ 65″ 550 4 33.5 37,2 36.6 35.7 35.5 37.0 36.6 400 750 65″ 85″ 50″ 50″ 85″ 85C 14 34.5 36.3 35.5 36.8 36.4 36.8 36.8 700 950 70″ 1150 45″ 550 750 850 21 36.
34.6 37.7 35.8 36.8 36.3 37.5 37.7 95″ 950 70″ 1300 40″ 600 950 550 28 33.8 35.5 34.0 37.2 35.3 37.5 36.4 100″ 1100 700 110″ 550 800 90″ 750 35 22 34.2 36.2 35.3 36.3 36.5 39.4 39.2 1000 950 750 1150 750 750 75″ 750 42 34.0 35.5 34.5 39.3 34.0 38.8 40.0 950 1000 105″ 550 750 550 Lmeness Trea tmen t 6 3 Control 1 I
I
a C CO C CO a a a 000 0 a 0 0 a o a Trea tmen t 2 5 6 Parameter I tii(F Inches’, 161.5 163. 1 16t.3 157.3 160.4 157.7 145.4 -1 T’-p .I-7 76.1 126.7 145.7 i 148.8 1.35.8 149.2 106.5 ,I/SE .9 145.2 142.5 I’1 155.0 156.9 123.6 142.9 163.8 133.3 145.3 153.4 168.2 128.5 143.7 160.7 144.9 28 15§.40 155.4 164.7 35 156.8 159.8 165.2 147.1 164.7- 159.0 4? T 7U 162.6 169.3 167.1 128.2 151.7 165.0 145.9 Control 4
I
7 74.5 139. 5 100.9 130.0 152.1 152.0 139.3 At 7ero Indicates t.5at the borse did not put the aff~cted foot to the paper m~easuredI.
thus no stride could be r o, c 0
I,
D 0, a 0 4″4 0a p *1u 0*s 4l 04 00 0C 22 Analyses of these results were plotted for each parameter along with some data on the intra-articualr treatment of horse joints similarly traumatized by the injection of Freund’s Complete Adjuvant. However, the induced trauma was somewhat less severe than that of the present study so the control horses from this study had a range of motion not too different than the treatment horses of the present study. But, more importantly, the difference in recovery of range of’ motion and lameness between( treatment and control horses for the present study closely paralleled that observed in the earlier study. Thus, the effects obtained by intramuscular injection were highly similar to those previously obtained by intra-articular administration.
These analyses are displayed in Figures 1 through 6. In these figures the open squares represent the average values for the four treatment horses and the open triangles represent the average values for the four control horses of this study. The hexagons and shaded ,20 squares represent the average values for horses with a similarly induced joint trauma who were treated intra-articularly with a single dose of 40 and milligrams, respectively, of a similar aqueous sodium hyaluronate solution while the shaded triangles 25 represent the average values for the untreated control horses used in this earlier study.
Figure 1 displays the change in the “joint circumference” from the day before the first injection until the end of the study forty three days later (for convenience the “day value has been plotted on the 0 axis and represents the increase in joint circumference (in inches) since the day before the traumatizing injection, i.e. day Although the joint swelling is never completely reversed, it is stabilized at a lower Mo-2817 I i 23 level or partially alleviated by hyaluronic acid treatment. The effect is somewhat less dramatic with the present (intramuscular) route of administration but is clearly present and is on joints which were indicated by the other parameters to be more severely traumatized than those treated intra-articularly.
Figure 2 displays the chang in the “range of motion” (ROM) over the same time period as Figure The 100% value is based on the ROM displayed the day before traumatization, i.e. on day, It is clear that the joints evaluated in the comparison intra-articular study were less traumatized because te inhibition of the ROM before treatment was less severe.
It is also clear that the intramuscular and the intra-articular treatments have caused parallel improvements over their respective controls. However, because the Freund’s Complete Adjuvant causes an extreme trauma neither the inventive or the comparison treatment could completely alleviate the induced condition.
Figures 3 and 4 display further analyses of the ROM data wherein the percent of improvement over the 4, condition the day before the first treatment injection is evaluated. The time scale is the same as in Figures 1 and 2. In Figure 4 the graph has been arbitrarily adjusted upward by adding 23.7% to all ordinate values.
Here it appears that che present invention’s .4 intramuscular administration results in. a greater °41 improvement over its control than in the case of the 0 intra-articular administration.
30 Figure 5 displays the change of the “observed lameness” over the same period as the previous figures.
SThe intramuscular and the intra-articular routes of administration displayed approximately equivalent effects. The controls for the present study showed a Mo-2817 4 r 24 somewhat higher degree of lameness suggesting that the traumatization for the present study was somewhat more severe than for the prior intra-articular study. The fact that the same level of lameness was obtained from both routes of administration suggests the route of the present invention might be somewhat more effective.
Figure 6 displays the change in “stride lenigth” over the same time period as the previous Figures. The stride at each evaluation was compared to the average value displayed the day before the traumatizing injection, i.e. day to obtain a percentage of recovery. The horses treated according to both the present invention and intra-articular injection show a faster and greater ultimate recovery of stride compared to their respective controls.
EXAMPLE 2 Back pain in a man aged 48, weight 155 pounds was alleviated by topical application of an aqueous solution of sodium hyaluronate mixed with 10 to 20 volume per cent of dimethyl sulfoxide (DMSO) In particular preparations were made up with 10, 20 and volume per cent of DMSO and the balance a 1,7 weight per cent solution of sodium hyaluronate with a 37°C viscosity of in excess of 500 c/s and a FPLC determined molecular weight of 2 x 106 daltons with a nucleic acid content of 0.00137 mg/ml and a total amino acid content by orthophthlalldehyde fluorescence of 0.0047 mg/ml.
Applications of about 2 ml of preparation were made to the back in the vicinity of the pain twice daily for a period of two weeks. In each case the pain was relieved in about 15 minutes and the relief lasted about 8 to hours. Treatment was then suspended and the pain returned in about four to five days. At this time treatment was resumed by the daily application of about 0 0 ao4 0 00 0 0 a0 00 4 0 4 S0 04 Mo-2817 25 2 ml of the preparation to the knuckles of the hands with effective relief of the pain. This treatment was discontinued af-er three days and the pain did not reoccur in the next two and a half weeks. Thus, the pain was effectively treated with a topical dose of about 0.15 milligrams per pound of body weight (2ml x 1.7 wt. x 70 vol. x 1000 mg/ml) applied either in the vicinity of the pain or at a more remote location.
The pain relieved by this treatment had been close to constant for about two years before treatment was initiated. After treatment the pain was observed at a much lower intensity only after sitting or sleeping in a constant position for a prolonged period, The topical application of the sodium hyaluronate without a transdermal carrier was ineffective. The hyaluronate solution simply evaporated to dryness leaving a film on the skin of the subject.
The application of equivalent amounts of DMSO alone was ineffective to relieve the back pain. In 20 fact, it caused some irritation of the skin area to which it was applied. This was in distinct contrast to the application in combination with the sodium hyaluronate solution in which no skin irritation was observed.
9n 9 9 a 9 9p 9 9.
99r 9 o0 99 o 9 9 e~C EXAMPLE 3 Various joint and muscle pains were relieved in S a man age 54 weighing 250 polnds by the topical 9 application of the same aqueous sodium hyaluronate used in Example 2 combined with 20 volume per cent of DMSO, based on total volume. A knee causing pain from several year old cartilage damage w&t. treated with 4 milliliters of this preparation and relief was observed within minutes. Treatment was repeated on four day intervals to successfully control the pain for about two weeks.
Mo-2817 M I I 26 Bursitis pain in a shoulder was successfully alleviated within a few minutes on the topical application of about ml of this same preparation. Pain returned in about four days and was relieved by the same treatment. The cycle was repeated four tir’ Pain from sore muscles in the clavicle region was relieved by the application of 3 milliliters of this preparation. Application was made to one side only and pain persisted in the untreated side.
EXAMPLE 4 A severe back pain in a man age 57 weighing 195 Ibs. who had multiple prolapsed disc in the lumbar area causing muscle spasms was relieved by the topical application of 2 milliliters of the preparation described in Example 2 with 20 volume per cent DMSO.
The preparation was applied to the skin over the lumbar spine and relieved the pain within one hour for approximately eight hours. The treatments were continued on twelve hour intervals for a period of several days with an occassionally skipped treatment.
On some occassions the treatment was not effective but Sin such cases the subsequent” treatment was effective.
The condition being treated had been treated by enzyme injection therapy more than a year previously.
Elective surgery was being considered at the time the present treatment was initiated.
SEXAMPLE S° Two quarter horses, normally actively engaged So in barrel racing, developed tendonitis of the flexor tendons of both hind legs and were successfully treated by topical application of the aqueous sodium hyaluronate solution of Example 2 mixed with a transdermal carrier.
The 80 volume percent hyaluronate/20 volume percent dimethyl sul.foxide mixture was more effective than a Mo-2817 -27 commercially available topical agent, Absorbine, One leg of each horse was treated with hyaluronate mixture and the other was treated with the Absorbine. The hyaluronate was applied twice each day for three days using three milliliter applications the first day and one milliliter application the subsequent two days (in each case i of each application was applied on each side of the leg). At the end of three days the symptous, swelling over the tendon and sheath and soreness over the sesamoid bones, were eliminated. The primary lesion was gone. On the other hand, treatment with Absorbine in the recommended manner re juired six days of treatment for complet relief.
COMPARATIVE EXAMPLE 1 Two experiments were conducted which demonstrated a limitation in the remote administration of hyaluronic acid. Two of the control horses from the 0 study reported in Example 1 were treated topically and two others were treated intravenously after their joint O 20 traumas had become chronic and no significant improvement in their conditions was observed. Although o« some relief of a chronic condition induced bv Freund’s Complete Adjuvant has been reported for the intra-articular injection of sodium hyaluronate in European Published Patent Application 144,019 this model is commonly restricted to the evaluation of the treatment of acute conditions. The lesions developed an extended period after traumatization are so severe that So they are not normally expected to respond to treatment.
Thus, these results are not judged to be a major limitation on remote administration and may, in fact, only be r’eflective of the severity of the induced trauma.
Mo-2817
F.~
I
28 The topical treatment was given on a daily basis for six days beginning on “day 28” of the Example 1 study, i.e. thirty-four days after the induction of trauma, by the application of ten milliliters of a 80 volume percent hyaluronate volume percent dimethyl sulfoxide mixture to the affected joint. The aqueous hyaluronate solution was the same as utilized in Example 2. No significant improvement in any of the four criteria of Example 1 were observed as compared to either the immediate pretreatment condition or the other two control horses.
The intravenous treatment was given every other day for eight days beginning on “day 35” of the Example 1 study, i.e. forty-one days after the induction of trauma, by injection into the jugular vein of four milliliters of the aqueous sodium hyaluronate solution used in Example 1. Once again no significant improvement in any of the four criteria was observed.
Although the invention has been described in 20 detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for .o that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
u4 Sa a 9 0 o *a Mo-2817

Claims (11)

1. A process for reducing the inflammation, pain or other result of trauma in irritated mammalian tissue comprising administering to a mammal, topically, subcutaneously, intramuscularly or intraveneously, an effective dose of hyaluronic acid or a pharmacologically acceptable salt thereof at a site in or on the b dy of the mammal remote from said tissue. i it

2. The process of Claim 1 wherein the dose is at least 0.044 S mg. per kilogram of body weight of the subject being treated.

3. The process of Claim 1 wherein the dose is at least 0.088 S* mg per kilogram of body weight of the subject being treated.

4. The process of Claim 1 wherein the hyaluronic acid is administered by an injection route as an aqueous 0.5 to co 0 weight per cent solution having a 37 0 C viscosity of less than °2 200 c/s.

5. The process of Claim 1 wherein the hyaluronic acid has an FPLC determined molecular weight distribution lying almost «c entirely between 1.5 and 4 million daltons. 9 0

6. The process of Claim 1 wherein the hyaluronic acid is 0 non-pyrogenic and by UV absorbance at 280nm has a combined amino acid and protein content of less than 1.25 mg/ml and by UV absorbance at 257nm has a nucleic acid content of less than 0.06 mg/ml.

7. A process for at least partially alleviating inflammation or soreness or both of a horse joint comprising the ST iS ntramuscular injection of an approximately one weight percent 135g I–l I 30 aqueous solution of sodium hyaluronate having a 370 solution viscosity below 200 c/s and a FPLC determined molecular weight distribution which is a single significant peak lying between about 1.5 and 4.0 million daltons at a dose of at least 0.088 mg of hyaluronate per kilogram of horse body weight.

8. The process of Claim 1 wherein the hyaluronic acid is administered topically in combination with a transdermal carrier.

9. The process of Claim 8 whetein the hyaluronic acid is between 0.5 and 3.0 weight percent aqueous solution and is mixed with up to 30 volume percent of a transdermal carrier.

10. A process for reducing the inflammation, pain or other result of trauma in irritated mammalian tissue, substantially ftt as herein described, with reference to Examples 2-4.

11. A process for at least partially alleviating inflammation S or soreness or both of a horse joint, substantially as herein described, with reference to Examples 1 and DATED this 29Th day of January 1990. o MOBAY CORPORATION By Its Patent Attorneys ARTHUR S. CAVE CO. S\0135g -S

AU71782/87A
1986-04-28
1987-04-15
Remote administration of hyaluronic acid to mammals

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not_active
Expired – Lifetime

1987

1987-03-31
CA
CA000533391A
patent/CA1314218C/en
not_active
Expired – Lifetime

1987-04-15
AU
AU71782/87A
patent/AU596838B2/en
not_active
Expired

1987-04-22
EP
EP87105907A
patent/EP0243867B1/en
not_active
Expired – Lifetime

1987-04-22
AT
AT87105907T
patent/ATE61523T1/en
not_active
IP Right Cessation

1987-04-22
DE
DE8787105907T
patent/DE3768546D1/en
not_active
Expired – Lifetime

1987-04-22
ES
ES87105907T
patent/ES2038135T3/en
not_active
Expired – Lifetime

1987-04-27
NZ
NZ220098A
patent/NZ220098A/en
unknown

1987-04-27
DK
DK212587A
patent/DK212587A/en
not_active
Application Discontinuation

1987-04-27
HU
HU871850A
patent/HUT43790A/en
unknown

1987-04-27
JP
JP62102113A
patent/JP2567393B2/en
not_active
Expired – Fee Related

1987-04-27
ZA
ZA872964A
patent/ZA872964B/en
unknown

1987-07-01
KR
KR1019870006850A
patent/KR950007233B1/en
not_active
IP Right Cessation

Patent Citations (3)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

EP0143393A2
(en)

1983-11-25
1985-06-05
Miles Inc.
The use of ultrapure hyaluronic acid to improve animal joint function

EP0161887A2
(en)

1984-05-04
1985-11-21
Seikagaku Kogyo Co. Ltd.
Crosslinked hyaluronic acid and its use

WO1986005989A1
(en)

1985-04-11
1986-10-23
Clinimed Limited
Medical syringe

Also Published As

Publication number
Publication date

CA1314218C
(en)

1993-03-09

ZA872964B
(en)

1987-10-20

EP0243867B1
(en)

1991-03-13

KR950007233B1
(en)

1995-07-07

AU7178287A
(en)

1987-10-29

DE3768546D1
(en)

1991-04-18

JPS62255428A
(en)

1987-11-07

ES2038135T3
(en)

1996-07-16

KR890001572A
(en)

1989-03-27

ATE61523T1
(en)

1991-03-15

NZ220098A
(en)

1991-06-25

DK212587A
(en)

1987-10-29

EP0243867A3
(en)

1988-03-23

JP2567393B2
(en)

1996-12-25

HUT43790A
(en)

1987-12-28

US4808576A
(en)

1989-02-28

EP0243867A2
(en)

1987-11-04

DK212587D0
(en)

1987-04-27

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