CROSS-REFERENCE TO RELATED APPLICATIONS

The present patent application claims the benefit and priority of U.S. Provisional Patent Application No. 62/975,293, filed on February 12, 2020, titled “CO-ADMINISTRATION OF PREDNISOLONE/METHYL PREDNISOLONE AND ZOLEDRONIC ACID TO TREAT AND PREVENT OSTEOARTHRITIS,” the contents of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods for treating and/or preventing osteoarthritis ("OA") by the intravenous co-administration of Zoledronic Acid or a pharmaceutically-acceptable salt thereof, and prednisolone and/or methyl prednisolone to a patient in need of treatment and/or prevention thereof. The dosage of prednisolone or methyl prednisolone is between 10 and about 50 mg, and, in one embodiment, is mixed with between about 4 and 5 mg of Zoledronic Acid or a pharmaceutically-acceptable salt thereof, and infused in normal saline.

BACKGROUND OF THE INVENTION

Zoledronic Acid, sold as Zometa/Aclasta/Reclast, is a nitrogen containing bisphosphonate that is used for treatment of hypercalcemia of malignancy, for the treatment of bone metastasis associated with malignancies such as prostate and breast cancer, for the prevention of and treatment of osteoporosis and for the treatment of Paget's disease. Zoledronic Acid is administered by an intravenous infusion of 4 mg every 3-4 weeks (Zometa) for multiple myeloma and bone metastasis of other malignancies or 5 mg once a year (Aclasta/Reclast) for non-oncologic indications. It is also used for the treatment of hypercalcemia of malignancy as needed.

Administration of Zoledronic Acid is complicated by what is described as "post-dosing syndrome" (PDS) which affects as much as 44% of patients. The syndrome is characterized by fever, nausea, bone pain, arthralgia, myalgia, chills, etc. In addition, administration of Zoledronic Acid leads to worsening of arthralgia in persons suffering from osteoarthritis. The etiology of this phenomenon has not been identified, but is associated with an increase in levels of tumor necrosis factor (TNF), interleukin 6 (IL-6), and gamma interferon (Dicuonzo G et al 2003, Schweitzer D H et al 1995, Thiebaud D et al 1997). These cytokines are usually produced by T cells. Zoledronic acid can cause stimulation of a subset of T cells known as gamma delta (y 6) T cells (Mariani S et al 2005). These cells, specifically V g 9/V g2 T cells, can constitute up to 10% of circulating CD3 T cells when stimulated. Upon stimulation by Zoledronic Acid, these g6 T cells produce interleukin 2 (IL-2) and TNF. IL-2 in turn can stimulate the production of other cytokines such as IL-6 and g IFN. Thus, treatment with Zoledronic Acid can stimulate a subset of T cells that may lead to post dosing syndrome by production and release of pro-inflammatory cytokines.

Osteoarthritis (OA) is the most common bone and joint disease influenced by genetic and environmental factors. Osteoarthritis is a debilitating disorder, affecting millions of patients a year. Many therapeutics used to treat osteoarthritis have to be given on a daily basis, and in some cases, many times a day, in order to provide relief. The continued administration of these therapeutic agents, including non-steroidal anti-inflammatory drugs (NSAIDS), can result in liver disorders and gastro-intestinal perforations over time. In addition, they can cause impairment of renal function. Other measures to treat OA include direct injection into the knee joint of hyaluronic acid which causes relief for three to six months. It cannot be used in any other joint except the knee joint. Intra-articular steroids are used to treat OA, but they have a transient effect and are ineffective when given by any route other than by the intra-articular route. Thus, oral, intravenous, rectal, inhaled and topical steroids are not useful for treatment of OA. All intra-articular therapies have the side effect of pain during injection and possibilities of joint infection. All these medications treat pain, but do not have any effect on the disease. Thus, there is no disease modifying agent to treat OA. It would be advantageous to provide additional treatments for osteoarthritis, which can be given less frequently, have fewer side effects, and be effective. Finally, a disease modifying drug would be very useful. In addition to those patients identified as suffering from osteoarthritis, there are also patients that are at a high risk of osteoarthritis. There are accepted medical tests to identify such patients. For example, association studies have uncovered the genetic factors behind OA, its susceptibility genes, which enables physicians to predict disease occurrence based on genotype information. The predictive assays can screen for a single susceptibility gene, or, more preferably, a combination of susceptibility genes. However, there are few available preventative treatments for patients at risk of developing osteoarthritis. It would be advantageous to have compositions and methods for avoiding the onset of post dosing syndrome. U.S. Patent No. 9,737,553 discloses compositions including zoledronic acid or a pharmaceutically acceptable salt thereof, and a steroid, where the steroid is administered in a dosage range equal to the equivalent of about 5 to about 50 mg of prednisolone. However, it would also be advantageous to optimize the amount of steroid to both minimize side effects, and maximize long-term relief from osteoarthritis, or prevention of the onset of osteoarthritis in patients identified as being at risk of developing osteoarthritis.

The present invention provides such compositions and methods.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to the co-administration of prednisolone or methyl prednisolone and Zoledronic Acid or a pharmaceutically-acceptable salt thereof to prevent or treat osteoarthritis. In one embodiment, the prednisolone or methyl prednisolone is administered intravenously, and in other embodiments, is administered orally, intramuscularly, via inhalation, as a suppository, or injected directly into a joint.

The co-administration of a steroid decreases the production of cytokines described above, and, therefore, decreases the pro-inflammatory effects of Zoledronic Acid. The co-administration of Zoledronic Acid with steroids treats osteoarthritis, and helps to prevent the onset of osteoarthritis in patients at risk for osteoarthritis. Existing osteoarthritis treatments are given frequently, for example, daily, or several times a day. In contrast, this combination can be given yearly, semi- yearly, quarterly, or monthly.

DETAILED DESCRIPTION

Compositions and methods for treating and preventing osteoarthritis are described. The compositions comprise Zoledronic acid or a pharmaceutically-acceptable salt thereof, and prednisone or methyl prednisolone, plus a pharmaceutically-acceptable diluent for intravenous administration. The amount of prednisolone/methyl prednisolone is between 10 and about 50 mg, for example, between 11 and 45 mg, between 15 and 40 mg, or between 20 and 35 mg.

Zoledronic Acid Zoledronic acid has the following formula:

Zoledronic Acid is often administered as the bisphosphate, and can be administered in the form of a pharmaceutically- acceptable salt.

Analogs of Zoledronic acid are disclosed, for example, in U.S. Pat. No. 4,939,130, and these analogs are also intended to be within the scope of the invention, and can be used in place of Zoledronic Acid in each embodiment of the invention described herein.

Pharmaceutically acceptable salts of Zoledronic acid, or the analogs disclosed in U.S. Pat. No. 4,939,130, include in particular the salts thereof with pharmaceutically acceptable bases, such as non-toxic metal salts derived from metals of groups la, lb, Ila and lib, e.g. alkali metal salts, preferably sodium or potassium salts, alkaline earth metal salts, preferably calcium or magnesium salts, copper, aluminum or zinc salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases such as free or C-hydroxylated aliphatic amines, preferably mono- , di- or tri-lower alkylamines, e.g. methylamine, ethylamine, dimethylamine or diethylamine, mono-, di- or tri(hydroxy-lower alkyl)amines such as ethanolamine, diethanolamine or triethanolamine, tris(hydroxymethyl)aminomethane or 2-hydroxy-tert-butylamine, or N- (hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower alkylamines such as 2-(dimethylamino)ethanol or D-glucamine, or quaternary aliphatic ammonium hydroxides, e.g. with tetrabutylammonium hydroxide.

Zoledronic Acid, as well as the analogs disclosed in U.S. Pat. No. 4,939,130, may also be obtained in the form of inner salts. These compounds can therefore also be converted into the corresponding acid addition salts by treatment with a strong protic acid such as a hydrohalic acid, sulfuric acid, sulfonic acid, e.g. methanesulfonic acid or p-toluenesulfonic acid, or sulfamic acid, e.g. N-cyclohexylsulfamic acid. As used herein, the term Zoledronic Acid is intended to also include pharmaceutically- acceptable salts thereof.

In one embodiment, Zoledronic Acid is administered as approved by the FDA, that is, by infusion, typically in infusions of around 4 to 5 mg infusions, once a year, or once every two years for post-menopausal women. In another embodiment, Zoledronic Acid is administered more frequently, for example, semi- yearly, quarterly, or monthly.

When administered as an infusion, the Zoledronic Acid is administered in a form suitable for intravenous administration to a human or other animal patient.

As used herein, "suitable for intravenous administration to a human or other animal patient" refers to an aqueous solution including Zoledronic acid and one or more pharmaceutically acceptable excipients, such as salt, which forms a saline solution. Solutions that are suitable for intravenous administration to a human or other animal patient do not include excipients that would compromise the health of a patient. For example, certain organic solvents (e.g., dimethyl sulfoxide, ethanol, propanol, acetone, and dimethyl formamide) are miscible in water and useful for the preparation of aqueous solutions of insoluble compounds. However, these organic solvents are poisonous at certain concentrations, so should not be administered intravenously to a patient at harmful concentrations. Furthermore, solutions that are suitable for intravenous administration to a human typically have a pH of between 4 and 9. Accordingly, the solutions may be buffered as appropriate, for example, using phosphate-buffered saline.

By "infusion" is meant a continuous intravenous administration of Zoledronic Acid, or other compound of Formula I, or a pharmaceutically-acceptable salt thereof, over a period of greater than five minutes, wherein the compounds are ideally administered at a constant or near constant rate.

In one aspect of this embodiment, patients are supplemented with calcium and/or vitamin D, if dietary intake is not sufficient. Whether or not supplementation is desired can be readily determined by a physician.

In another aspect of this embodiment, to prevent glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months, Zoledronic Acid is administered in a 5 mg intravenous infusion once a year, given over no less than around 5 minutes, preferably no less than around 15 minutes. To prevent osteoporosis in postmenopausal women, the Zoledronic Acid is administered in a 5 mg intravenous infusion given once every 2 years intravenously over no less than 15 minutes. Accordingly, the frequency of dosing can be once every two years for post-menopausal women. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of 1200 mg calcium and 800 to 1000 International Units of vitamin D daily.

However, in other embodiments, the Zoledronic Acid is administered by injection. Zoledronic Acid has a half-life (tl/2a) of about 0.24 hours, and its administration is known to be associated with certain side effects in a large subpopulation of patients. The co-administration of steroids helps to minimize or eliminate these side effects. By "co-administration," it is meant that the steroids can be administered within two hours before or after the Zoledronic acid, typically within one hour before or after the Zoledronic acid, and, more typically, at the same time, or within a half an hour before or after the Zoledronic Acid.

Prednisone/Methyl Prednisolone

The steroids administered with the zoledronic acid or pharmaceutically- acceptable salt thereof are prednisolone and/or methylprednisolone, administered in a dosage of between 10 and about 50 mg. The zoledronic acid or pharmaceutically-acceptable salt thereof, and prednisolone and/or methylprednisolone, are administered intravenously. The administration of the prednisolone and/or methylprednisolone can occur either at the same time the zoledronic acid or pharmaceutically-acceptable salt thereof is administered, or within about two hours before or after the zoledronic acid or pharmaceutically-acceptable salt thereof is administered. More typically, the prednisolone and/or methylprednisolone are administered within one hour before or after the Zoledronic acid or pharmaceutically-acceptable salt is administered, and, more typically, at the same time, or within a half an hour before or after the Zoledronic Acid or pharmaceutically- acceptable salt is administered.

Additional Therapeutic Agents

Additional therapeutic agents can be administered, either via intravenous administration, along with the zoledronic acid or pharmaceutically-acceptable salt thereof and/or the prednisolone or prednisolone, or via a different mode of administration.

For example, analgesics and anesthetics can be administered. The anesthetic is any compound that is capable of blocking nerve impulses from the area of discomfort to the brain. Representative anesthetics include local anesthetics such as marcaine, procaine (novocaine), chloroprocaine (nesacaine), cocaine, lidocaine, tetracaine (amethocaine, pontocaine), mepivacaine, etidocaine (duranest), bupivacaine (marcaine), dibucaine (cinchocaine, nupercaine), prilocaine (citanest), benzoxinate (dorsacaine), proparacaine (alcaine, opthaine and opthetic), benzocaine (anesthesin), butamben (butesin), oxybuprocaine, pramoxine, proxymetacaine, and Alpha-2 adrenergic receptor agonists such as Dexmedetomidine and Propofol.

The choice of anesthetic will depend on the type of discomfort to be alleviated and is generally known to those skilled in the art of anesthesia. For example, lidocaine and marcaine are commonly injected, along with cortisone or hydrocortisone, directly into joints.

In addition to administration of additional therapeutic agents when the Zoledronic acid or a pharmaceutically-acceptable salt thereof is administered, a patient can supplement the treatment by taking glycosaminoglycans, such as hyaluronic acid, glucosamine, chondroitin, and the like. These glycosaminoglycans are typically administered in an oral formulation, such as a pill, tablet, capsule, and the like, and hyaluronic acid can be injected along with the Zoledronic Acid, or pharmaceutically-acceptable salts thereof, and the steroid, directly into the knee, shoulder (particularly, the rotator cuff), the lumbar spine, and other joints, if desired.

Methods of Treatment

To treat a patient suffering from osteoarthritis, a patient can be intravenously administered a combination of Zoledronic Acid or a pharmaceutically-acceptable salt thereof, and prednisolone and/or methyl prednisolone. To obtain the maximum efficacy, the treatment should be initiated in patients with early stages of osteoarthritis ("OA") pathogenesis, or at least as early as possible.

The administration can be, for example, once a year. In one embodiment, the Zoledronic Acid and prednisolone and/or methyl prednisolone are administered by simultaneous intravenous administration, and in another embodiment, are administered in separate intravenous administrations.

The methods can be used, for example, to treat or prevent osteoarthritis in the knee, shoulder, elbow, hip or back. In one aspect of this embodiment, 10 mg of prednisolone or methyl prednisolone can be dissolved with or combined with about 4 to about 5 mg of Zoledronic Acid, or a pharmaceutically acceptable salt thereof, in an appropriate vehicle for injection, such as Normal Saline or Phosphate Buffered Saline (up to 100 cc) by swirling gently in room temperature for one minute. This mixture is ideally used within 5 minutes of mixing if kept at room temperature, or within an hour if kept in a refrigerator, so as to minimize the possibility of having a precipitate form.

In another embodiment, the prednisolone and/or methyl prednisolone is intravenously administered up to two hours, more typically, within one hour, and most preferably, within a half hour, of the intravenous administration of the Zoledronic acid or pharmaceutically-acceptable salt thereof.

In another embodiment, in addition to the Zoledronic Acid or pharmaceutically-acceptable salt thereof, and the prednisolone and/or methyl prednisolone, an anesthetic is administered shortly before or after the combination of the Zoledronic Acid or pharmaceutically-acceptable salt thereof and prednisolone/methyl prednisolone.

Representative anesthetics for this embodiment include lidocaine and Marcaine.

In one embodiment, in addition to prednisolone/methyl prednisolone, an additional steroid can be administered, in addition to the anesthetic. Representative steroids for this embodiment include cortisone, hydrocortisone, and pharmaceutically acceptable salts thereof. In one aspect of this embodiment, the additional steroid is administered directly into the joint.

In one embodiment, rather than administering the prednisolone/methyl prednisolone intravenously, it is administered orally or intra-articularly.

Methods for Predicting the Onset of Osteoarthritis

The methods described herein for treating osteoarthritis can also be used to prevent the onset of osteoarthritis for patients at risk of developing osteoarthritis.

To obtain the maximum efficacy, treatment should ideally be initiated when the patient is early stages of OA pathogenesis (see, for example, Yu et al., "Efficacy of zoledronic acid in treatment of osteoarthritis is dependent on the disease progression stage in rat medial meniscal tear model," Acta Pharmacol Sin. 2012 July; 33(7):924-34). Accordingly, it can be useful to identify patients at risk of developing osteoarthritis, and minimize the damage to their joints. Numerous methods are described in the literature for predicting osteoarthritis, in man and in other mammals. These methods include, for example, assessments of joint mobility, and genetic testing using known alleles predictive of osteoarthritis. For example, methods for predicting osteoarthritis of the hip in Labrador retrievers are taught in Corfield, et al., "Assessment of the hip reduction angle for predicting osteoarthritis of the hip in the Labrador Retriever," Aust Vet J. 2007 June; 85(6):212-6. Methods for predicting osteoarthritis of the hip in humans are taught, for example, in Birrell et al., "Predicting radiographic hip osteoarthritis from range of movement," Oxford Journals Medicine Rheumatology, Volume 40, Issue 5 Pp. 506-512. Restriction in range of movement was predictive of the presence of OA in new presenters to primary care with hip pain, and the results of this examination can be used to inform decisions regarding treatment with the methods described herein.

Methods for predicting osteoarthritis of the knee are described, for example, in Takahashi et al., "Prediction model for knee osteoarthritis based on genetic and clinical information," Arthritis Research & Therapy 2010, 12:R187. Osteoarthritis (OA) is the most common bone and joint disease influenced by genetic and environmental factors. Recent association studies have uncovered the genetic factors behind OA, its susceptibility genes, which enable one to predict disease occurrence based on genotype information. The prediction can be based on the effects of only a single susceptibility gene, or using OA-prediction models based on more than one gene. Risk alleles that can be assessed include the three susceptibility genes, asporin (ASPN), growth differentiation factor 5 (GDF5), and double von Willebrand factor A domains (DVWA). Clinical information, as well as the number of risk alleles, can be used for OA prediction.

The present invention will be better understood with reference to the following non limiting examples.

EXAMPLE 1: Treatment of Osteoporosis Patients with Zoledronic Acid and Steroids

Eight patients with osteoporosis were treated with a single infusion of Zoledronic Acid (ZA) alone (four patients) or with a single infusion of the combination of prednisolone and Zoledronic Acid (ZP, four patients). All four patients who received Zoledronic Acid suffered from PDS. In contrast, none of the patients receiving ZP suffered from PDS.

Of the 8 subjects, five had osteoarthritis. Of these five, three were treated with ZP and two with Zoledronic Acid. All three subjects treated with ZP had a decrease in joint pain (VAS scale) six months after the single infusion and one subject up to one year after the single infusion. In the Zoledronic Acid arm, both subjects had the same (one) or worse (one) level of pain than before the single infusion.

In a further study, this one, a single blind, single center study, 20 subjects with knee osteoarthritis were randomized to either intravenous ZP or ZA in a 1:1 ratio. Subjects were followed for six months. Efficacy was measured by change in pain in 100 mm visual analogue score (VAS) from baseline (mean values). Patients were asked about the level of pain without taking rescue medications (NSAIDS or tramadol). Bone mineral density (BMD) was determined at baseline and six months to detect any effect on bone.

ZP was clearly more effective in controlling OA pain than ZA alone, with the added benefit of no post-dosing symptoms. The efficacy could not have been the result of Prednisolone, since IV Prednisolone by itself has no effect on arthritis pain, which is why steroids are not given orally or intravenously for osteoarthritis (only intra-articularly ² ).

In addition, the effect of Prednisolone is transient, less than a day, and so cannot account for the analgesic effect six months out. The effect of ZA was similar to that seen in the earlier study.

Example 2: Comparison of the Effect of Different Prednisolone Dosages

Zoledronic Acid, 5 mg, with 10 mg methylprednisolone was compared in a head to head study against Zoledronic Acid, 5 mg with 5 mg methylprednisolone. Designed to overcome the side effect profile of Zoledronic Acid, especially post-dose symptoms, the study was conducted in eight subjects over a period of six months. Based on the label, it was expected that approximately 50% of subjects in each arm would suffer from post-dose symptoms.

Subjects were randomized to receive 5 mg Zoledronic Acid/5 mg methylprednisolone or 5 g Zoledronic Acid/ 10 mg methylprednisolone in a one to one ratio.

Of the ten subjects who received 5 mg Zoledronic Acid/5 mg methylprednisolone, six had arthralgia, two had myalgia, one had headaches, and one had fever post infusion within 48 hours of the drug administration. The incidence was higher than expected at 100%.

In contrast, of the ten subjects who received 5 mg Zoledronic Acid/10 mg methylprednisolone, not a single subject had any post dose symptoms including headaches, fever, myalgia or arthralgia. As a result, it appears that a dose of 5 mg of methylprednisolone is not ideal for countering the side effect profile of Zoledronic Acid, and that 10 mg of methylprednisolone is an effective dose.

Larger doses of prednisolone/methyl prednisolone can be used, up to around 50 mg.

REFERENCES

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2. Schweitzer D H, Oostendorp-van de Ruit M, Van der Pluijm G et al. Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen- containing bisphosphonate dimethylaminohydroxyl-propylidene bisphosphonate. J Bone Miner Res 1995; 10: 956-962.

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8. Corfield, et al. Assessment of the hip reduction angle for predicting osteoarthritis of the hip in the Labrador Retriever. Aust Vet J. 2007 June; 85(6):212-6.

9. Birrell et al. Predicting radiographic hip osteoarthritis from range of movement. Oxford Journals Medicine Rheumatology, Volume 40, Issue 5 Pp. 506-512.

10. Takahashi et al. Prediction model for knee osteoarthritis based on genetic and clinical information. Arthritis Research & Therapy 2010, 12:R187 The contents of all references described herein are incorporated herein by reference in their entirety for all purposes.

The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.