Controlled release compositions and their methods of use

Abstract

The present invention relates to a composition, the composition including a therapeutically effective amount of at least one active agent, and a base including, an amount of colloidal silica; at least one oil; and at least one surfactant, wherein the viscosity of the composition is below 1000 mPas at a shear rate of 100 l/s and at a temperature of 20 C.

Claims

1. A controlled release composition comprising: a therapeutically effective amount of at least one active agent, wherein the active agent is an antibiotic, at least one preservative, and an excipient base that provides a controlled release of the at least one antibiotic, wherein the excipient base consists of hydrophobic colloidal silicon dioxide at a concentration between 0.1-5% w/w; at least one oil; and at least one non-ionic surfactant, wherein the surfactant has a hydrophilic-hydrophobic balance (HLB) between 0.5 and 30, and wherein the concentration of surfactant is between 0.01 to 10% w/w; wherein the viscosity of the composition is below 300 mPas at a shear rate of 100 1/s and at a temperature of 20 C., and wherein the composition does not contain hydroxystearin.

2. The composition as claimed in claim 1, wherein the at least one antibiotic is selected from the group consisting of a beta-lactam, penicillin, cephalosporin, aminoglycoside, quinolones, sulphonamides, tetracyclines and macrolide antibiotic.

3. The composition as claimed in claim 1, wherein the at least one antibiotic is selected from the group consisting of cloxacillin or a functional derivative thereof, tylosin or a functional derivative thereof, cephapirin or a functional derivative thereof, and combinations thereof.

4. The composition as claimed in claim 1, wherein the composition comprises at least two antibiotics or the at least one antibiotic and at least one non-antibiotic active agent.

5. The composition as claimed in claim 4, wherein the at least two antibiotics or the at least one antibiotic and at least one non-antibiotic active agent is selected from the group consisting of: amoxicillin and clavulanic acid; penicillin active agent and aminoglycoside; cloxacillin and tylosin; and an antibiotic and a non-steroidal anti-inflammatory drug.

6. The composition as claimed in claim 1, wherein the at least one antibiotic is micronised.

7. The composition as claimed in claim 1, wherein the colloidal silicon dioxide is fumed colloidal silicon dioxide.

8. The composition as claimed in claim 1, wherein the concentration of colloidal silicon dioxide is between 1-3% w/w.

9. The composition as claimed in claim 1, wherein the surfactant has a hydrophilic-hydrophobic balance (HLB) between 4 and 16.

10. The composition as claimed in claim 1, wherein the non-ionic surfactant is selected from the group consisting of sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyethylene oxide monooleate and combinations thereof.

11. The composition as claimed in claim 1, wherein the ratio of colloidal silicon dioxide to surfactant in the base is between 1:100 and 500:1.

12. The composition as claimed in claim 1, wherein the ratio of colloidal silicon dioxide to surfactant in the base is between 1:5 and 6:1.

13. The composition as claimed in claim 1, wherein the base includes more than one surfactant.

14. The composition as claimed in claim 1, wherein the viscosity of the oil is between 1 to 100 mPas at 20 C.

15. The composition as claimed in claim 1, wherein the viscosity of the oil is less than 40 mPas at 20 C.

16. The composition as claimed in claim 1, wherein the oil is selected from the group consisting of medium chain triglycerides, light liquid paraffin, ethyl oleate and sesame oil.

17. The composition as claimed in claim 1, wherein the density of the oil is between 0.80 and 0.99 g/cm.sup.3.

18. The composition as claimed in claim 1, wherein the composition has a viscosity below 150 mPas at a shear rate of 100 1/s and temperature of 20 C.

19. A method of manufacturing a composition as claimed in claim 1 comprising the steps of: a) mixing the oil and surfactant in a container to form a homogenous oil mixture; b) dispersing the active agent in the oil mixture; and c) subsequently adding the colloidal silicon dioxide to the oil mixture.

20. A method of treating a non-human animal in need thereof with a composition as claimed in claim 1 comprising administering the composition to the animal by intramammary infusion.

21. The method as claimed in claim 20 comprising administering 1-6 doses of 5 g formulation composition over a period of 0 to 120 hours administered 324 hours or 624 hours.

22. The method as claimed in claim 20 for the treatment or prevention of mastitis during the lactation period of a non-human animal.

23. The composition as claimed in claim 1, which is non-aqueous.

24. The composition as claimed in claim 1, which comprises from 2 w/w-% to 9.18 w/w-% of the at least one antibiotic.

25. The composition as claimed in claim 1, wherein the at least one antibiotic is cloxacillin or a functional derivative thereof.

26. The composition as claimed in claim 1, wherein the composition maintains the minimum inhibitory concentration wherein 90% of the microbes are killed (MIC90) during the entire treatment period until the next dose.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) Further aspects of the present invention will become apparent from the ensuing description which is given by way of example only and with reference to the accompanying drawings in which:

(2) FIG. 1 Comparison of dynamic viscosities between mastitis treatment compositions (lactation period treatment)

(3) FIG. 2 Influence of surfactant on active agent recovery rate (in vitro)

(4) FIG. 3 Influence of surfactant on active agent recovery rate (in vitro)

(5) FIG. 4 Influence of colloidal silica concentration on active agent recover rate (in vitro)

(6) FIG. 5 Influence of colloidal silica type (hydrophobic vs hydrophilic) on active agent recovery rate (in vitro)

(7) FIG. 6 Influence of oil on active agent recovery rate (in vitro)

(8) FIG. 7 Exemplification of cloxacillin bioavailability in tissues 2 hours after treatment (in vivo)

(9) FIG. 8 Influence of active agent type on active agent concentration in milk (in vivo)

(10) FIG. 9 Influence of active agent type on active agent concentration in milk (in vivo)

(11) FIG. 10 Influence on composition characteristics on WHP (in vivo)

(12) FIG. 11 Influence on the number of treatments of example composition 1 on WHP (in vivo)

(13) FIG. 12 WHP determination of Example 1 composition based on ACVM guidelines (in vivo)

(14) FIG. 13 Comparison of treatment between Example 1 composition and NitroClox LA (in vivo)

(15) FIG. 14 Comparison of WHP between Example 1 composition and NitroClox LA (in vivo)

(16) FIG. 15 Comparison of treatment between Example 1 composition and Orbenin LA (in vivo)

(17) FIG. 16 Comparison of WHP between Example 1 composition and Orbenin LA (in vivo)

BEST MODES FOR CARRYING OUT THE INVENTION

(18) Part 1: Example Compositions

(19) TABLE-US-00001 Example 1 mg w/w-% Cloxacillin sodium 231 4.62% Methyl paraben 3.75 0.075% Propyl paraben 1.25 0.025% Aerosil R972 Pharma 87.5 1.75% Span 80 25 0.50% Miglyol 812 4651.5 93.03% Total 5000 100.00%

(20) TABLE-US-00002 Example 2 mg w/w-% Cephapirin sodium 220.9 4.42% Methyl paraben 3.75 0.075% Propyl paraben 1.25 0.025% Aerosil R972 Pharma 87.5 1.75% Span 80 25 0.50% Miglyol 812 4651.5 93.03% Total 5000 100.00%

(21) TABLE-US-00003 Example 3 mg w/w-% Cloxacillin sodium 231 4.62% Aerosil R972 Pharma 100 2.00% Span 80 25 0.50% Miglyol 812 4644 92.88% Total 5000 100.00%

(22) TABLE-US-00004 Example 4 mg w/w-% Cloxacillin sodium 231 4.62% Aerosil R972 Pharma 150 3.00% Span 80 100 2.00% Miglyol 812 4519 90.38% Total 5000 100.00%

(23) TABLE-US-00005 Example 5 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 87.5 1.75% Span 80 100 2.00% Miglyol 812 4354 87.07% Total 5000 100.00%

(24) TABLE-US-00006 Example 6 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% PEG12Oleate 5 0.10% Miglyol 812 4423.5 88.47% Total 5000 100.00%

(25) TABLE-US-00007 Example 7 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% PEG12Oleate 2.5 0.05% Miglyol 812 4426 88.52% Total 5000 100.00%

(26) TABLE-US-00008 Example 8 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% Span 80 2.5 0.05% Miglyol 812 4426 88.52% Total 5000 100.00%

(27) TABLE-US-00009 Example 9 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% Span 80 5 0.10% Miglyol 812 4423.5 88.47% Total 5000 100.00%

(28) TABLE-US-00010 Example 10 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% Span 80 25 0.50% Miglyol 812 4403.5 88.07% Total 5000 100.00%

(29) TABLE-US-00011 Example 11 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% Span 80 50 1.00% Miglyol 812 4378.5 87.57% Total 5000 100.00%

(30) TABLE-US-00012 Example 12 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 112.5 2.25% Span 80 100 2.00% Miglyol 812 4328.5 86.57% Total 5000 100.00%

(31) TABLE-US-00013 Example 13 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 150 3.00% Span 80 100 2.00% Miglyol 812 4291 85.82% Total 5000 100.00%

(32) TABLE-US-00014 Example 14 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil 200 Pharma 150 3.00% Span 80 100 2.00% Miglyol 812 4291 85.82% Total 5000 100.00%

(33) TABLE-US-00015 Example 15 mg w/w-% Cloxacillin sodium 459 9.18% Aerosil R972 Pharma 150 3.00% Span 80 100 2.00% Peanut Oil 4291 85.82% Total 5000 100.00%

(34) TABLE-US-00016 Example 16 mg w/w-% Cloxacillin sodium 200 2.00% Tylosin base 250 2.50% Aerosil R972 Pharma 400 4.00% Span 80 200 2.00% Methyl paraben 0.4 0.004% Propyl paraben 0.2 0.002% Miglyol 812 8949.4 89.49% Total 10000 100.00%

(35) TABLE-US-00017 Example 17 mg w/w-% Cloxacillin sodium 437 8.74% Aerosil R972 Pharma 150 3.00% Span 80 100 2.00% Methyl paraben 0.4 0.008% Propyl paraben 0.2 0.004% Miglyol 812 4312.4 86.25% Total 5000 100.00%

(36) Note that the cloxacillin sodium used in Examples 1-17 (and also Example 18 shown below) are in a micronised form.

(37) Part 2: Exemplification of Controlled Release Rate of Active Agent

(38) FIG. 1 illustrates the comparatively low viscosity of the preferred composition of the present invention compared to reference products currently on the market. Recovery rates in dissolution media (shown in FIGS. 2-6) are considered by the inventors to be indicative of in vivo release rates.

(39) FIG. 2 clearly illustrates one of the major advantages of the present invention. Compared to Orbenin LA, the two test compositions in FIG. 2 have very low viscosity (90-150 mPas vs 1080 mPas). Orbenin LA is able to maintain a relatively slow cloxacillin release (approximately 5%) by using a thickener (hydroxystearin). This viscosity of Orbenin LA compared to the current compositions can be visualised in FIG. 1.

(40) The two test compositions depicted in FIG. 2 do not include a thickener to impart a slow recovery profile. Instead, careful selection of the surfactant (Span80 vs. PEG12-oleate) can be used to significantly alter the recovery profile of the cloxacillin without a significant rise in the viscosity. The test composition containing PEG12-oleate has a recovery profile substantially identical (if not slower) than Orbenin LA, yet the viscosity beneficially remains relatively low (180 mPas).

(41) FIG. 3 illustrates that the recovery rate of the active agent can be affected not only by the choice of the surfactant type, but also the concentration thereof. This is exemplified by the increase of the concentration of Span80 (HLB=4.3) from 0.05% to 1% (Examples 8 to 11). Only a small rise in the viscosity is seen, yet a disproportionate decrease in the active recovery is provided.

(42) Similarly, alteration of the concentration of PEG12-Oleate (HLB=13.7) (Examples 6 and 7) is shown, with corresponding changes in the recovery profile. Therefore, this illustrates that different types and concentrations of surfactants may be used to control the release profile of compositions in vivo.

(43) FIG. 4 illustrates that the concentration of colloidal silica also affected recovery rates of the active agent. It was found that as the concentration of colloidal silica (in this case Aerosil R972) increased from 1.75% to 3% w/w, the recovery rate was lowered.

(44) Again, although the recovery profile slowed dramatically as the silica concentration increased from 1.75 to 3%, the viscosity only increased slightly from 90 mPas to 127 mPas.

(45) FIG. 5 illustrates that the type of colloidal silica may also affect the recovery rate of the active agent. Here, hydrophobic colloidal silica (Aerosil R972) is shown to significantly lower the recovery rate compared to hydrophilic colloidal silica (Aerosil 200). This is despite the hydrophobic silica imparting a lower viscosity on the composition compared to the same composition using hydrophilic silica. This is contrary to the common understanding in the art.

(46) FIG. 6 illustrates that the type of oil used may also affect the recovery rate of the active agent.

(47) FIG. 7 illustrates the distribution of cloxacillin in different tissues two hours after treatment. In this case tissue is defined as remaining udder directly after milking, which includes extracellular liquid, blood vessels, and potentially some remaining milk which is not milked out.

(48) FIGS. 8 and 9 illustrates how different active agents can also have an affect on the release profile of the active agent itself, all else being substantially equal. In FIG. 8, when cloxacillin in the example composition 1 is replaced with cephapirin (as shown in example composition 2), the release profile is substantially slowed. In FIG. 9, differences were also seen between cloxacillin and tylosin. This was indeed a surprising result and suggests that the active's release may be influenced by an interaction with a possible structural network formed with some or all of the excipients in the composition's base.

(49) FIGS. 10-14 illustrate how the WHP of the composition may be affected by the characteristics of the composition.

(50) FIG. 10 illustrates how an increase in the amount of colloidal silica from 1.75% to 3.00% w/w can alter the WHP significantly.

(51) FIG. 11 illustrates that the number of treatments does not affect WHP. The WHP is approximately equal regardless of whether the animal is treated with a 624 hour or 324 hour regime.

(52) FIG. 12 illustrates the calculated WHP of example 1 composition according to ACVM (Agricultural Compounds & Veterinary Medicines) guidelines.

(53) FIG. 13 illustrates the effectiveness of example 1 composition versus NitroClox LA. Of particular interest is that after each treatment, the amount of active agent is higher when administered with the example 1 composition than NitroClox LA, suggesting a higher bioavailability of example 1, 24 h after treatment. Similar to NitroClox LA, the example 1 composition does not decrease below the MIC90 (solid line) 24 h after treatment, yet is more rapidly removed from the milk after the final treatment at 0 hrs.

(54) FIG. 14 reflects the results shown in FIG. 13. The example 1 composition is calculated to have a WHP of only 72 hours compared to 108 hours for NitroClox LA.

(55) FIG. 15 compares the example 1 composition to Orbenin LA, albeit with a different treatment regime (64 hours vs. 348 hours, respectively). It can be seen that although the treatment regime using example 1 composition provides a much longer and consistent level of active agent in the milk than the treatment regime using Orbenin LA, the active agent is released from the milk much quicker after the final treatment. As can be seen, the final treatment of OrbeninLA is at 96 hours, whereas the final treatment with example 1 composition is at 120 hours; providing a longer treatment period. FIG. 16 illustrates that the calculated WHP is 12 hours and 24 hours shorter in the example 1 composition's 624 hour treatment regime compared to Orbenin's 348 hour and 524 hour treatment regimes, respectively.

(56) Part 3: Manufacturing Method

(57) a) Mix Miglyol 812, methyl paraben, propyl paraben and Span 80 well to form homogeneous oil mixture. b) Sterilise the mixture at 140 C. for 3 hours and then cool to room temperature. c) In a separate container, load the required amount of Aerosil R972 Pharma. d) Sterilise at 140 C. for 3 hours and then cool to room temperature. e) Disperse and homogenise the cloxacillin sodium into the sterilised oil mixture. f) Disperse the sterilised Aerosil R972 Pharma into the sterilised oil suspension. g) Homogenise the mixture.
Part 3: Animal Study

(58) As part of a study commenced in November 2011, the Example 18 formulation, as detailed below, was investigated for efficacy in the treatment of bovine mastitis.

(59) TABLE-US-00018 Example 18 mg w/w-% Cloxacillin sodium 229.2 4.584* Methyl paraben 3.75 0.075 Propyl paraben 1.25 0.025 Sorbitan mono-oleate (Span 80) 25 0.5 Hydrophobic silica (Aerosil R972 87.5 1.75 Pharma) Fractionated coconut oil (Miglyol812N) 4653.3 93.066 Total 5000 100 *5% overages added

(60) The animals used in the study were dairy cows diagnosed with clinical mastitis. On day 0, milk samples were obtained for bacteriological analysis and the animals were treated with intramammary infusions of Example 18 three times, with each treatment 24 hours apart. The dose for each treatment was 200 mg of cloxacillin as the sodium salt.

(61) On days 28 and 35, further milk samples were obtained for bacteriological analysis to determine the cure rate. A successful bacteriological cure required the animal to be clinically cured of mastitis, and for the pathogen identified in the day 0 sample to be absent in the day 28 and day 35 samples.

(62) Interim results available as of 1 Nov. 2012, provided a bacteriological cure proportion of 69.6% when treated with Example 18, from 100 cows enrolled with clinical mastitis, and with gram positive bacteria identified at the time of enrolment.

(63) A comparable study is that reported by M D Wraight, New Zealand Veterinary Journal 51(1), 26-32, 2003 A comparative efficacy trial between cefuroxime and cloxacillin as intramammary treatments for clinical mastitis in lactating cows on commercial dairy farms. In this study, 200 mg of cloxacillin in a long-acting formulation was administered as an intramammary every 48 hours for three treatments, which resulted in a bacteriological cure proportion of 64.3%.

(64) The interim study results on Example 18 demonstrate high efficacy of compositions of the invention, even when compared to more intensive long-acting treatments using the same active. This indicates that obtaining an advantageous, shorter withhold period by using compositions of the invention, does not reduce or compromise the efficacy of the treatment.

(65) Part 4: Formulation Stability

(66) A stability study was conducted on three batches of Example 18. These batches were packed into 5 mL polyethylene syringes and stored at designated storage temperatures and humidity conditions of 25 C./60% RH, 30 C./65% RH and 40 C./75% RH. The physical and chemical characteristics of the batches were recorded at regular intervals as recommended by ACVM. Based on the stability data, at a storage temperature of 25 C. a shelf life of at least 18 months is expected.

(67) Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims.