WO1999051201A1

WO1999051201A1 - Sustained release formulation

Info

Publication number: WO1999051201A1
Application number: PCT/NZ1999/000037
Authority: WO
Inventors: Ian George Tucker; Majid Hameed Abdul Razzak; Colin Manson Harvey
Original assignee: Ashmont Holdings Limited
Priority date: 1998-04-03
Filing date: 1999-04-01
Publication date: 1999-10-14
Also published as: AUPP279698A0

Abstract

An implant formulation for the sustained release of a biologically active agent, including an effective amount of abamectin dissolved in or mixed with a carrier such as PEG 20000 which is solid or semi-solid at normal room temperature and pressure, but which melts at temperatures between 35 °C and 100 °C. An implant for delivering said formulation into a human or animal body and a method of making said implant and in addition a method for providing for the sustained release of an active agent into a human or animal body.

Description

SUSTAINED RELEASE FORMULATION

FIELD OF THE INVENTION This invention relates to formulations for delivering biologically active agents to a human or an animal, and in particular it relates to sustained release formulations which may be implanted into a human or an animal for the prolonged delivery of a biologically active agent.

BACKGROUND

For many biologically active agents a preferred form of dosage is by means of the sustained release of the agent into the animal to be treated. A variety of polymeric implants are useful as delivery systems, but there is an ongoing need for improved delivery systems to be available for the treatment of both humans and animals.

It is particularly important in the treatment of livestock that biologically active agents can be administered for a prolonged period by way of a single dose, thereby avoiding the mustering of stock at regular intervals.

In particular the avermectins and milbemycins are anthelmintic groups of drugs with a broad spectrum of activity against many parasites found in livestock. At present they are usually administered as either a sub-cutaneous injection, an oral drench, or a pour- on. These forms of administration are not designed to deliver the anthelmintic agent over a prolonged period of time, and consequently blood levels of the anthelmintic are not sustained. This results in a limited period of anthelmintic activity and the need to dose the animals frequently to obtain ongoing and complete protection. Frequent dosing of livestock is onerous under pastoral conditions. Consequently, a formulation which, with one dose, could sustain the blood levels of the anthelmintic over a prolonged period would be of great value. One difficulty is that avermectins and milbemycins are very insoluble, and generally dissolve too slowly when administered under the skin to be useful. If they are first dissolved in an oil the rate of release can be - 2 - increased, but the maximum period of protection obtainable by this method may be up to only 20 days, and regular treatment would still be required.

OBJECT It is an object of the present invention to provide an improved formulation for the sustained delivery of a biologically active agent, or at least to provide the public with a useful choice.

STATEMENT OF INVENTION In one aspect the invention comprises a formulation for the sustained release of a biologically active agent, including an effective amount of at least one biologically active agent dissolved in and/or mixed with a carrier, said carrier being a substance which is solid or semi-solid at normal room temperature and pressure, but which melts in range of 35 to 100°C. Preferably the biologically active agent is an anthelmintic.

Preferably the carrier is a polymer having a molecular weight greater than 1000.

More preferably the carrier is present in the range from 20% w/w to 80% w/w.

Preferably the active agent is present in the range from 20% w/w to 80% w/w.

In a related aspect the invention comprises a solid or semi-solid implant for the sustained release of the biologically active agent, said implant including an effective amount of at least one biologically active agent dissolved in and/or mixed with a carrier, said carrier being a substance which is solid or semi-solid at normal room temperature and pressure, but which melts in the range 35 to 100°C.

Preferably the solid or semi-solid implant is adapted to provide an initially high rate of release of the biologically active agent for a short time, followed by a slower rate of release at a prolonged period of time. - 3 -

More preferably the active is present in the implant at a level of 50% w/w or greater and the carrier is present at a level of 20% w/w or greater.

More preferably the implant is designed to be inserted subcutaneously.

In a further aspect the invention provides a method of providing for the sustained release of a biologically active agent into a human or animal body, which includes placing a solid or semi-solid implant into said body, said implant including an effective amount of at least one biologically active agent dissolved in and/or mixed with a carrier, said carrier being a substance which is solid or semi-solid at normal room temperature and pressure, but which melts in the range 35 to 100°C.

By wet granulation is meant the process whereby the active agent, in powder form, is mixed thoroughly with the carrier polymer, which has previously been dissolved in water. Wet granules are formed, which are then dried. The granules may then be blended with the usual excipients used in the formation of tablets. Magnesium stearate and Aerosil 200, are known in this regard. Other additives may also be added at this point. This mixture can then be compressed into tablets or implants having the desired weight and size by using well-known techniques.

By melt granulation is meant a process essentially similar to wet granulation, but in this case the active agent, in powder form, is optionally warmed, and then mixed with the carrier polymer which has been warmed and melted.

It has been found that the most suitable carriers are solid or semi-solid at 35°C and melt below 100°C. If the temperature at which the carrier melts becomes too high then there is a danger that, in the formation of the implant, the biological activity of the active ingredient will be destroyed.

While a variety of polymers are suitable for the formulation of the invention, both polyvinyl pyrrolidone, (PVP), or polyethylene glycol, (PEG) are known to be suitable, especially when the biologically active agent is an anthelmintic, and in particular, abamectin. A number of PEG polymers of the general formula H(OCH₂CH₂)_nOH exist, - 4 - and the most suitable for this invention are those with an average molecular weight greater than about 1000, in particular PEG 1500, PEG 2000, PEG 4000, PEG 6000 and PEG 20000.

It has been found that by carefully controlling the ratio of the polymer to the biologically active agent the rate of release of the active can be controlled. In particular it has been found that by reducing the percentage of a carrier such as PEG to below about 40% w/w but preferably below 20% w/w and increasing the percentage of the active agent, such as abamectin, to above about 60% w/w and preferably to about 80% w/w, an initially large amount of the active agent is released for the first 10 to 20 days, followed by a lower amount being steadily released over a prolonged period of time.

It is thought that when the implant is formed, some, but not all, of the active agent dissolves in the carrier polymer. The active agent which is dissolved is released relatively quickly, as the polymer enhances the availability of it to the human or the animal body. When all the polymer has gone, the remaining active agent, which was not dissolved, continues to be released more slowly on the basis of its physical and chemical properties. If the active agent belongs to the group of the avermectins or milbemycins, the insoluble nature of the compound becomes an advantage as the release of the active agent is relatively slow as a consequence.

The rate of release of the active dissolved in the carrier can be varied by selecting a carrier with a higher or lower melting point, for example PEG 20000 instead of PEG 1500.

It is envisaged that the rate of release of the active, not dissolved in the carrier, can be enhanced, if necessary. The dissolution rate of any active can be engineered or manipulated by various well-known techniques, making it possible to optimise the release rate of the active agent by applying those techniques in conjunction with the known physical properties of the active agent. Micronisation of the active powder, inclusion of a surfactant, and the use of a disintegrating agent are three such techniques. In particular, it appears that the highly insoluble nature of abamectin is advantageous in this context, in that it assists in the slower, subsequent release of this active, and it allows for optimisation of the rate of its release in conjunction with the techniques available, especially micronisation and the use of a disintegrating agent or surfactant.

It is particularly desirable that the carrier is biodegradable. If this is the case then once all the biologically active agent has been released there should be no residue left within the body of the animal or human, allowing for the successive use of implants without any long term detrimental effects.

The most suitable biologically active agents are those with a high activity and low required dose rate. Examples of biologically active agents which could be used, either singly or in combination, are: anthelmintics, anti-inflammatories, anti-bacterials, anti- parasitic agents, anti-virals, anti-fungals, analgesic agents, vaccines and others.

PREFERRED EMBODIMENTS

The above and other aspects of the invention which should be considered in all its novel aspects will be apparent from the following examples.

Example 1.

An implant having a total weight of 250mg, and a diameter of 5mm, and a thickness of about 3mm, was prepared from 50mg of abamectin and 200mg PEG 2000, (20% w/w abamectin, 80% w/w PEG 2000). The implant was prepared by melt granulation and granulation. The implant is suitable for subcutaneous insertion in the ear of an animal.

Example 2.

An implant as described in Example 1 , but containing 125mg of abamectin and 125mg PEG 2000, (50% w/w abamectin and 50% w/w PEG 2000). Example 3.

An implant as described in Example 1 , but containing 167.5mg of abamectin and 82.5mg PEG 20000, (67% w/w abamectin and 33% w/w PEG 20000).

Example 4.

An implant as described in Example 1 , but containing 200mg of abamectin and 50mg

PEG 20000, (80% w/w abamectin and 20% w/w PEG 20000).

Example 5.

An implant as described in Example 4 containing 200mg of abamectin and 50mg PEG 20000, (80% w/w abamectin and 20% w/w PEG 20000), but which has been prepared by means of wet granulation and compression.

Example 6.

An implant as described in Example 3 containing 167.5mg of abamectin and 82.5mg PEG 20000, (67% w/w abamectin and 33% w/w PEG 20000), but which has been prepared by means of wet granulation and compression.

Example 7

An implant having a total weight of 250mg, and a diameter of 5mm, and a thickness of about 3mm, was prepared from 50mg of ivermectin and 200mg PEG 20000, (20% w/w ivermectin, 80% w/w PEG 20000). The implant was prepared by melt granulation and granulation. The implant is suitable for subcutaneous insertion in the ear of an animal.

Example 8.

An implant as described in Example 7, but containing 125mg of ivermectin and 125mg

PEG 20000, (50% w/w ivermectin and 50% w/w PEG 20000).

Example 9. - 7 -

An implant as described in Example 7, but containing 167.5mg of ivermectin and 82.5mg PEG 20000, (67% w/w ivermectin and 33% w/w PEG 20000).

TRIAL DATA 1. Selection of Polymer

Initial trials were conducted to select the most suitable polymers for the in vivo animal studies to be conducted. These triais lead to the selection of PEG (polyethylene glycol) and PVP (poiyvinyl pyrrolidone) as the most promising polymers to be used. The trials investigated the release of abamectin from a series of formulations with different percentages of carrier to abamectin. The first set focussed on PVP as the carrier, the second used PEG. For the purposes of this study PEG 20000 was used. The results are displayed in Figures 1 and 2 respectively.

Figure 1 : Abamectin release as a function of time at different PVP concentrations.

— ♦— 0%PVP

8 - -»-33%FVP

-A-50%FVP

» 6 H -K-66%PVP

E ^•o -*-80%FVP

! • A ^ ,-

•

^ 2 ^ c

0 0

Ω i

24 48 72 96

Time (hr.)

Figure 2: Abamectin release as a function of time at different PEG concentrations.

_0% PEG - 25 .33.3% PEG .50% PBS .80% FB3

24 48 72 .96 Time (hr.) -8

Based on these results it was decided to use only PEG 20000 for the in vivo study.

2. In Vivo Testing of Implants - First study

Three formulations, A, B, and C were initially selected and prepared for study. Implants weighing 250mg and about 5mm in diameter were prepared from the formulations, and implanted into the base of the ear of a sheep. The compositions of A, B and C were.

A - 20% w/w abamectin and 80% w/w PEG 20000

B - 50% w/w abamectin and 50% w/w PEG 20000

C - 67% w/w abamectin and 33% w/w PEG 20000

All the formulations were prepared by melt granulation.

The following TABLE 1 and associated graph, give the concentration of active in the plasma, in ng/mL over days 3 to 70

Table 1 Concentration of abamectin in plasma (nq/rr lϋ

Day 3 7 14 21 35 49 70

Formul Sheep a

A 1 10 194 147 67 154 56 16

2 52 41 119 102 109 65 16

3 35 47 194 20 109 111 299

Mean ± 62±34 94±87 153*3 123±6 124±2 77±30 20±08 SD 8 9 6

B 1 205 194 140 180 86 56 16

2 194 176 188 127 109 56 40

3 14 141 160 167 147 56 52

Mean ± 147±9 170±2 162±2 158±2 114±3 56±0 36±18 SD 2 7 4 8 1

C 1 52 247 318 127 79 47 29

2 105 176 99 60 56 0 0

3 82 88 37 60 2.6 11 0

Mean ± 80±27 170±8 151±4 82±39 54±39 19±25 10±17 SD 0 8

- 9

Table 2 Pharmakokmetic Parameters of Abamectin Implants

Parameters Formulation A Formulation B Formulation C

Cmax (ng/mL) 17.0±4.4 18.8±2.1 19.4±11.6

Tmax (days) 14±7 9±10 9±4

AUC ng mL^"1 day 641.5+122.9 721.2±19.2 415.2±237.9

Figure 3 Time Course for Abamectin Implant

time (Days)

3. In vivo Testing of Implants - Second Study

Group 1 : two implants, 33mg abamectin and 20% PEG 20000. Group 2: three implants, 50mg abamectin and 20% PEG 20000. Group 3: two implants 33mg abamectin and 20% PEG 20000. Group 4: three implants 50mg abamectin and 20% PEG 20000.

Group 1 and 2 used small abamectin particles whereas those used in Groups 3 and 4 were large. 10

Table 3 The plasma abamectin concentration (nq/mL) versus time data for each sheep

Day 0 2 4 8 15 21 35 49 87

Shee

P

Group 1 00 26 22 286 195 124 20 04 68

1^* 2 00 06 11 114 105 158 48 60 00

3 00 26 19 80 285 135 31 41 00

4 00 09 08 100 141 268 240 88 00

Group 1 00 60 28 76 312 246 133 105 00 2 2 00 71 195 454 216 178 57 78 00

3 00 40 40 304 239 144 68 48 71

4 00 274 54 129 183 215 51 71 00

Group 1 00 43 106 233 334 215 113 75 22 3 2 00 37 09 152 177 144 59 25 00

3 00 08 12 112 350 113 74 60 86

4 00 12 08 00 337 383 133 67 61

Group 1 00 20 12 60 175 189 98 46 00 4 2 00 12 23 102 249 266 253 129 56

3 00 16 25 79 247 155 98 92 00

4 00 37 40 56 216 264 77 46 00

^* Value of abamectin concentration are mean, n=2

Table 4 Pharmacokinetics Parameters of Abamectin Implant

Parameters Group 1 Group 2 Group 3 Group 4

Cmax 249±61 26.2±54 22.8±10.9 22.6±4.5 (ng/mL) Tmax (day) 157±71 14.3±6.2 18.0±3.5 19.5±3.0 AUC 636.2+249.1 168.5±187.2 726.1±172.3 895.6±381.7 11 -

Table 5 Eqq counts

Groups Sheep Day 0 Day 2 Day 4 Day 8 Day 15 Day 21 Day 35 Day 49 Day 87 Code No

1.1 167 5 0 0 0 5 15 15 90 15

1.2 155 35 10 15 0 15 25 5 5 10

1.3 150 105 10 10 0 155 55 10 0 10

1.4 166 5 0 70 5 5 10 10 5 45

Mean 37.5 5 23.75 1.25 45 26.25 10 25 20

S.D 472 58 315 25 735 202 41 434 168

% 1258 1155 1325 2000 1633 768 408 1736 842

Variation

2.1 163 60 5 0 5 5 45 10 100 5

2.2 164 0 0 0 5 0 0 0 0 15

2.3 160 5 0 0 0 0 0 0 25 0

2.4 165 0 50 0 0 10 5 5 0 5

Mean 16.25 13.75 0 2.5 3.75 12.5 3.75 31.25 6.25

S.D. 293 243 00 29 48 218 48 473 63

% 1801 1766 00 1155 1277 1744 1277 1514 1007

Variation

3.1 156 100 10 0 10 5 0 0 0 30

3.2 162 0 5 5 0 10 5 5 0 55

3.3 161 10 0 0 0 25 0 0 0 5

3.4 154 25 15 0 5 10 5 5 20 20

Mean 33.75 7.5 1.25 3.75 12.5 2.5 2.5 5 27.5

S.D. 453 65 25 48 87 29 29 100 210

% 1344 861 2000 1277 693 1155 1155 2000 764

Variation

41 152 10 5 0 5 185 0 0 0 30

4.2 158 20 10 55 0 10 0 0 10 15

4.3 157 10 5 20 5 5 5 5 0 25

4.4 151 20 0 10 0 60 15 15 25 35

Mean 15 5 31.25 2.5 65 5 5 8.75 36.25

S.D 58 41 239 29 838 71 71 118 85

% 385 816 1126 1155 1289 1414 1414 1350 325

Variation

Control 153 130 235 80 75 475 125 100 125 135

1 Control 159 65 145 105 65 305 155 160 75 155

2

Mean 59.8 116.4 80.4 64.6 248.2 107.1 102.1 86.7 82.8

S.D. 527 978 401 466 1788 678 682 564 730

881 840 499 721 721 633 667 651 882

Variation

- 12

Fig 4: The mean plasma concentration of abamectin (n=4) after the dosing abamectin implant from the four formulations studied.

Day

ADVANTAGES OF PREFERRED EMBODIMENTS

In the sustained delivery of biologically active agents, and in particular anthelmintics, it is often desirable to have a large amount of the active agent released initially, followed by a smaller amount released steadily over a prolonged period of time. In the past it has only been possible to achieve two different rates of release of an active agent by means of two tablets sandwiched together. In certain of the preferred embodiments of this invention it is now possible to achieve this dual rate of release from a single dosage, by way of the implant of this invention.

In particular it has been discovered that biologically active agents such as avermectins or milbemycins, can be formulated into a single sustained release formulation in which the active is able to be released slowly over a prolonged period of time, but which may also deliver an initial boost of the biologically active agent in the immediate period after dosing. - 13 -

VARIATIONS

In addition to changing the ratio of the active to carrier, the rate of release of the active can also be manipulated by changing the carrier to one with a higher or lower melting point. This will affect the rate of dissolution of the carrier and consequently the rate of release of the dissolved active.

The active in the formulation may be micronised or alternately a disintegrating agent may be included in the formulation. This would help prolong the activity of the non dissolved active. Alternately the release in the second phase may be prolonged by delaying the release of PEG by using a higher molecular weight PEG, complexing the

PEG or using a coat which is released after 40 to 50 days.

Alternatives to PEG may be useful in prolonging this second phase.

Finally it will be appreciated that various other alterations and modifications may be made to the foregoing without departing from the scope of the invention.

Claims

- 14 - WHAT WE CLAIM IS:

1. A formulation for the sustained release of a biologically active agent, including an effective amount of at least one biologically active agent dissolved in an/or mixed with a carrier, said carrier being a substance which is solid or semi-solid at normal room temperature and pressure, but which melts in the range of 35 to 100┬░C.

2. A formulation as claimed in claim 1 wherein, the biologically active agent is an anthelmintic.

3. A formulation as claimed in any prior claim wherein the carrier is a polymer having a molecular weight greater than 1000.

4. A formulation as claimed in any prior claim wherein the carrier is present in the range from 20% w/w to 80% w/w.

5. A formulation as claimed in any prior claim wherein the active agent is present in the range from 20% w/w to 80% w/w.

6. A solid or semi-solid implant for the sustained release of the biologically active agent, said implant including an effective amount of at least one biologically active agent dissolved in and/or mixed with a carrier, said carrier being a substance which is solid or semi-solid at normal room temperature and pressure, but which melts in the range 35 to 100┬░C.

7. An implant as claimed in claim 6 wherein, the solid or semi-solid implant is adapted to provide an initially high rate of release of the biologically active agent for a short time, followed by a slower rate of release at a prolonged period of time.

8. An implant as claimed in claim 7 wherein the active is present at a level of 50% w/w or greater and the carrier is present at a level of 20% w/w or greater. - 15 -

9. An implant as claimed in claims 6, 7, or 8 wherein the implant is designed to be inserted subcutaneously.

10. A method of providing for the sustained release of a biologically active agent into a human or animal body, which includes placing a solid or semi-solid implant into said body, said implant including an effective amount of at least one biologically active agent dissolved in and/or mixed with a carrier, said carrier being a substance which is solid or semi-solid at normal room temperature and pressure, but which melts in the range 35 to 100┬░C.