AU2018101354A4 - Method of treatment - Google Patents

Abstract

Abstract The present invention relates to methods and compositions for increasing bone mineral density (BMD) and uses thereof. The compositions, in one embodiment comprising: between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium p-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH 4Cl), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H80) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w)

Description

METHOD OF TREATMENT

Field of the Invention [0001] The present invention relates generally to a composition for increasing bone mineral density (BMD) and uses thereof.

Background of the Invention [0002] The skeleton is a metabolically active organ that undergoes continuous remodelling throughout life. Bone remodelling involves the removal of mineralised bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralised. The remodelling cycle consists of three consecutive phases: resorption, during which osteoclasts digest old bone; reversal, when mononuclear cells appear on the bone surface; and formation, when osteoblasts lay down new bone until the resorbed bone is completely replaced.

[0003] Remodelling, therefore, removes old bone and replaces it with new bone. This regenerative process occurs within distinct areas of bone known as bone metabolic units (BMUs). Within each BMU bone formation by osteoblast and bone resorption by osteoclasts is coupled in tightly regulated feedback loop to maintain bone mass (/.<?., BMD) and strength and resist deformity. The aging process shifts this regulatory mechanism in a negative direction, favouring greater bone resorption and less bone formation. This combination of bone mass deficiency and reduction in strength increases the risk of osteoporosis and fractures.

[0004] Aging in combination with intrinsic and extrinsic factors can accelerate the decline in BMD. Intrinsic factors include genetics, peak bone mass accrual in youth, alternations in cellular components, hormonal, biochemical and vasculature status. Extrinsic factors include nutrition, physical activity, co-morbid medical conditions and drugs.

[0005] Strategies for minimising BMD loss include moderating physical activity with the onset of advanced age, supplementation with high doses of dietary calcium, both with and without vitamin D, avoiding alcohol and tobacco and use of bone absorption inhibitors to reduce the impact of the natural bone remodeling process. Hormone replacement therapy is also commonly prescribed to prevent bone loss in postmenopausal women; however, there is an associated risk of breast and endometrial cancer. Other therapeutic strategies that have been considered include calcitonin, biophosphonates, steroids and sodium fluoride. However, these therapeutics have been associated with negative side effects that can often prevent their long-term usage.

[0006] Accordingly, there is a need to develop new therapeutics and methods for increasing BMD.

Summary of the Invention [0007] In a first aspect, the present invention provides a method for increasing bone mineral density (BMD) in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water.

[0008] In a second aspect, the present invention provides a method for the treatment of low BMD in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water.

[0009] In an embodiment, the pharmaceutical composition comprises 0.06% (w/w) NaF, 0.1% (w/w) Na2FPO, 0.1% (w/w) disodium β-glycerophosphate, 0.2% (w/w) NH4CI, 0.2% (w/w) C7H8O and 0.002% (w/w) I, made up to 100% (w/w) with distilled water.

[0010] In another aspect disclosed herein, there is provided use of a composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water, in the manufacture of a medicament for increasing bone mineral density (BMD) in a subject in need thereof.

[0011] In an embodiment, the pharmaceutical composition is administered orally. In another embodiment, the pharmaceutical composition is administered orally to the subject in an amount from about 0.5 and 1 mL/kg at least once per day.

[0012] In an embodiment, the subject has a T-score of 1 to 2.4 SD below the young adult mean (-1 to -2.5 SD) or a T-score of 2.5 SD or more below the young adult mean (greater than -2.5 SD).

Brief Description of the Figures [0013] Figure 1 illustrates (a) the total bone mineral density of a 57 year old male subject (baseline) as measured by DEXA scan; (b) the densitometry of the total skeletal bone mineral density of the 57 year old male subject; and (c) statistical comparison of the total skeletal bone density with young adult and age matched comparators.

[0014] Figure 2 illustrates (a) the bone density of the left femur of the 59 year old male subject; (b) the densitometry of the total bone mineral density of the left femur of the 59 year old male subject; and (c) statistical comparison of bone mineral density with young adult and aged matched comparators for the neck, upper neck, wards, trach and shaft.

[0015] Figure 3 illustrates (a) the bone density of the AP spine of the 59 year old male subject; (b) the densitometry of the total bone mineral density of the AP spine of the 59 year old male subject; and (c) statistical comparison of bone mineral density with young adult and aged matched comparators for the LI, L2, L3, L4, L1-L4 and L2-L4 vertebrae.

[0016] Figure 4 illustrates (a) the bone density of the left femur of the 64 year old male subject; (b) the densitometry of the total bone mineral density of the left femur of the 64 year old male subject; and (c) statistical comparison of bone mineral density with young adult and aged matched comparators for the neck, upper neck, wards, trach and shaft.

[0017] Figure 5 illustrates (a) the bone density of the AP spine of the 64 year old male subject; (b) the densitometry of the total bone mineral density of the AP spine of the 64 year old male subject; and (c) statistical comparison of bone mineral density with young adult and aged matched comparators for the LI, L2, L3, L4, L1-L4 and L2-L4 vertebrae.

Detailed Description of the Invention [0018] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. Any materials and methods similar or equivalent to those described herein can be used to practice the present invention.

[0019] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[0020] By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of". Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they affect the activity or action of the listed elements.

[0021] As used herein the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a molecule" includes a single molecule, as well as two or more molecules; reference to "an agent" includes one agent, as well as two or more agents; and so forth.

[0022] The present disclosure is predicated, at least in part, on the inventor's surprising finding that the administration of a composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water, is capable of increasing bone mineral density (BMD). It was also surprisingly found that long-term administration with the composition did not give rise to any adverse side effects.

[0023] Therefore, in an aspect of the present disclosure there is provided a method for increasing bone mineral density (BMD) in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water.

[0024] In an embodiment, the composition comprises 0.06% (w/w) NaF, 0.1% (w/w) Na2FPO, 0.1% (w/w) disodium β-glycerophosphate, 0.2% (w/w) NH4CI, 0.2% (w/w) C7H8O and 0.002% (w/w) I, made up to 100% (w/w) with distilled water.

Pharmaceutical composition [0025] The pharmaceutical composition may be prepared in a form for administration by any suitable route that allows for the delivery of the composition to the subject in a therapeutically effective amount. Suitable routes of administration will be known to persons skilled in the art, illustrative examples of which include enteral routes of administration (e.g., oral and rectal) and topical routes of administration (e.g., buccal, sublingual, vaginal, intranasal or by inhalation). In an embodiment, the pharmaceutical composition is prepared in a form for enteral administration. In a preferred embodiment, the pharmaceutical composition is formulated for oral administration. Thus, in an embodiment, the pharmaceutical composition disclosed herein is administered orally to the subject.

[0026] Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the composition; as a powder or granules; or as a solution or suspension in an aqueous phase. The composition may also be presented as a bolus, electuary or a paste. In a preferred embodiment, the composition is presented as an aqueous solution.

[0027] It should be understood that in addition to the ingredients particularly mentioned above, the compositions herein may also include other agents conventional in the art, having regard to the composition in question. For example, compositions suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavoring agents, disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.

[0028] The composition may also contain carriers, diluents and excipients. Details of pharmaceutically acceptable carriers, diluents and excipients and methods of preparing pharmaceutical compositions and formulations are provided in Remmingtons Pharmaceutical Sciences 18th Edition, 1990, Mack Publishing Co., Easton, Pennsylvania, USA.

[0029] The composition may further comprise pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH-adjusting and buffering agents. In an embodiment, the composition is pH-adjusted to between 5.5 and 6.5.

Bone Mineral Density [0030] As noted elsewhere, the present inventors have surprisingly found that administration of a pharmaceutical composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water, is capable of increasing bone mineral density (BMD). It was also surprisingly found that long-term administration with the composition did not give rise to any adverse side effects. Therefore, in an aspect disclosed herein, the present disclosure provides a method of increasing BMD in a subject in need thereof, said method comprising the administration of an effective amount of the pharmaceutical composition described herein.

[0031] In another aspect, the present invention provides a method for treating low BMD in a subject in need thereof, said method comprising administering an effective amount of the pharmaceutical composition as described herein.

[0032] The terms "bone mineral density" or "BMD" are used interchangeably herein and refer to a measure of bone density, reflecting the strength of bones as represented by calcium content. BMD is measured by bone densitometry using methods such as dual energy x-ray absorptiometry (DEXA), which provides a quantitative measurement of the amount of mineral present in bone. A decrease in BMD as measured by DEXA is the current method of diagnosing osteoporosis and predicting fractures (see, for example, Nevitt and Cummings (1993) Journal of the American Geriatrics Society, 41:1226).

[0033] The standard deviation (SD) is the difference between the BMD of the subject and that of healthy young adults (i.e., the T-score). Positive T-score values are indicative of bone that is stronger than normal; negative T-score values are indicative of bone that is weaker than normal. According to the World Health Organisation (WHO), a T-score within 1 SD (+1 or -1) of the young adult mean indicates normal bone density, a T-score of 1 to 2.4 SD below the young adult mean (-1 to -2.5 SD) indicates low bone mass (i.e., osteopenia), a T-score of 2.5 SD or more below the young adult mean (greater than -2.5 SD) indicates the presence of osteoporosis and a T-score of 2.5 SD or more below the young adult mean (greater than -2.5 SD) in the presence of one or more fragility fractures indicates the presence of established osteoporosis.

[0034] The term "subject" as used herein refers to mammals and includes humans, primates, livestock animals (e.g., sheep, pigs, cattle, horses, donkeys), laboratory test animals (e.g., mice, rabbits, rats, guinea pigs), companion animals (e.g., dogs, cats) and captive wild animals (e.g. foxes, kangaroos, deer). In a preferred embodiment, the subject is a human. In an embodiment, the subject has a T-score of 1 to 2.4 SD below the young adult mean (-1 to -2.5 SD) or a T-score of 2.5 SD or more below the young adult mean (greater than -2.5 SD)..

[0035] The term "effective amount" is used herein to refer to an amount of the pharmaceutical composition effective to elicit a therapeutic effect. Persons skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic amount to administer for the desired outcome. In general, the pharmaceutical composition, as disclosed herein, can be administered in a manner compatible with the route of administration and physical characteristics of the subject (including health status) and in such a way that it elicits the desired effect(s) (z.e., therapeutic effect). For example, the appropriate dosage of the pharmaceutical composition may depend on a variety of factors including, but not limited to, a subject's physical characteristics (e.g., age, body weight, sex). The quantity and spacing of individual dosages, if multiple dosages are required to induce the desired therapeutic effect, will also be considered in determining the effective amount of the pharmaceutical composition. In an embodiment, the effective amount of the pharmaceutical composition is determined according to the subject's weight.

[0036] It is expected that the effective amount will fall in a relatively broad range that can be determined through methods known to the person skilled in the art, having regard to some of the considerations above. An effective amount can be ascertained, for example, by measurement of BMD. The increase in BMD provided by the pharmaceutical composition herein described can be monitored to determine the need for an increased dose or volume of the pharmaceutical composition.

[0037] It will be apparent to persons skilled in the art that the optimal quantity and spacing of individual dosages, if required to induce the desired effect, can be determined, for example, by the form, route and site of administration, and the nature of the particular subject to be treated, as is described elsewhere herein. Optimum conditions can be determined using conventional techniques known to persons skilled in the art.

[0038] In some instances, it may be desirable to have several or multiple administrations of the pharmaceutical composition, as herein described. For example, the pharmaceutical composition may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times. The administrations may be in one day intervals or in hourly intervals. It will be apparent to persons skilled in the art that the optimal course of administration can be ascertained using conventional course of treatment or efficacy tests.

[0039] In an embodiment, the effective amount of the pharmaceutical composition is determined according to the subject's weight. In a preferred embodiment, the effective amount of the pharmaceutical composition is between about 0.5 and 1 mL/kg of body weight of the subject, to be administered to the subject at least once per day.

[0040] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is also to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The inventive also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

[0041] Certain embodiments of the invention will now be described with reference to the following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.

EXAMPLES

Comparative bone mineral density analysis [0042] Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA or DXA) scanning performed at The Alfred Hospital, Melbourne. T-scores were obtained from the BMD result by comparison with the BMD results from healthy 25-to 35-year old adults of the same sex and ethnicity and aged matched controls. The standard deviation (SD) is the difference between the BMD of the subject and that of healthy young adults (i.e., the T-score). Positive T-score values are indicative of bone that is stronger than normal; negative T-score values are indicative of bone that is weaker than normal. According to the World Health Organisation (WHO), a T-score within 1 SD (+1 or -1) of the young adult mean indicates normal bone density, a T-score of 1 to 2.4 SD below the young adult mean (-1 to -2.5 SD) indicates low bone mass, and a T-score of 2.5 SD or more below the young adult mean (greater than -2.5 SD) indicates the presence of osteoporosis.

[0043] For this comparative BMD analysis, a 50 year old patient received 50 mL per day of the pharmaceutical composition described in Table 1 via oral administration, with treatment commencing on 1 July 2001. The patient received no other course of BMD treatment during this study period.

Table 1. Pharmaceutical composition

[0044] The first BMD measurement was taken approximately 7 years after the commencement of treatment, when the patient was aged 57, a second BMD measurement was taken when the patient was aged 59 and a third BMD measurement taken when the patient was aged 64. The results of the consecutive BMD measurements are provided below in Table 2.

- 11 -

Table 2. BMD Results

[0045] The results of the first BMD measurement provide the baseline BMD for the head, arms, legs, trunk, ribs, pelvis and spine, with the statistical analysis and generation of T-score (young adult comparators) and Z-score (aged matched comparators) limited to the total BMD of each skeletal region. The results indicate that the legs (z.e., deemed equivalent to the left femur for the purpose of Table 1) have a BMD of 1.100 g/cm and the spine (z.e., deemed equivalent to the AP spine for the purpose of Table 1) has a BMD of 1.843 g/cm2.

[0046] Using these values as baseline for comparison with the subsequent BMD measurements, the results from the second measurement taken on the 25 January 2010 indicate a 14.3% increase in the BMD in the femur (Figure 2) and a 41.3% increase in BMD in the AP spine (Figure 3), by reference to BMD.

[0047] The increase in BMD observed at the second measurement was further increased at the third measurement taken in 2015, where the patient demonstrates an 80.7% increase in the BMD of the femur (Figure 4) and a 72.3% change in BMD in the AP spine (Figure 5), by reference to BMD from baseline. These data clearly show that the pharmaceutical composition is effective for increasing BMD.

Claims (5)

1. Claims

   1. A method for increasing bone mineral density (BMD) in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water.
2. 2. The method of claim 1, wherein the pharmaceutical composition comprises 0.06% (w/w) NaF, 0.1% (w/w) Na2FPO, 0.1% (w/w) disodium β-glycerophosphate, 0.2% (w/w) NH4CI, 0.2% (w/w) C7H8O and 0.002% (w/w) iodine (I), made up to 100% (w/w) with distilled water.
3. 3. The method of claim 1 or claim 2, wherein the pharmaceutical composition is administered orally to the subject in an amount from about 0.5 and 1 mL/kg at least once per day.
4. 4. The method of any one of claims 1 to 3, wherein the subject has a T-score of 1 to 2.4 SD below the young adult mean (-1 to -2.5 SD) or a T-score of 2.5 SD or more below the young adult mean (greater than -2.5 SD).
5. 5. Use of a composition comprising between about 0.05 and 0.07% (w/w) sodium fluoride (NaF), between about 0.09 and 0.11% (w/w) disodium monofluorophosphate (Na2FPO), between about 0.09 and 0.11% (w/w) disodium β-glycerophosphate, between about 0.18 and 0.22% (w/w) ammonium chloride (NH4CI), between about 0.18 and 0.22% (w/w) benzyl alcohol (C7H8O) and between about 0.001 and 0.0022% (w/w) iodine (I), made up to 100% (w/w) with distilled water, in the manufacture of a medicament for increasing bone mineral density (BMD) in a subject in need thereof.