SUBCUTANEOUSLY IMPLANTED DEVICE FOR GASTROINTESTINAL ADMINISTRATION OF SUBSTANCES

Abstract

A method includes using a subcutaneously-implanted pump to deliver to a portion of a gastrointestinal tract a formulation including a levodopa compound and a carbidopa compound which provides a treatment for a neurological disease, such as Parkinson’s disease.

Claims

1. A method of treating a neurological disease, comprising: using a subcutaneously-implanted pump to deliver to a portion of a gastrointestinal tract a formulation comprising a levodopa compound and a carbidopa compound which provides a treatment for a neurological disease.

2. The method according to claim 1, wherein a viscosity of said formulation is not greater than 50 centipoise at 30-41° C.

3. The method according to claim 1, wherein a viscosity of said formulation is in a range of 1-50 centipoise at 25° C.

4. The method according to claim 1, wherein said formulation also comprises an intestinal absorbance enhancer.

5. The method according to claim 1, wherein a ratio between the levodopa compound and the carbidopa compound is in a range of 3.5:1 - 10:1.

6. The method according to claim 1, wherein said levodopa compound is in a range of 300-1000 mg/ml and said carbidopa compound is in a range of 75-300 mg/ml.

7. The method according to claim 1, wherein said levodopa compound and said carbidopa compound constitute together at least 30% by weight of said formulation.

8. The method according to claim 1, wherein said levodopa compound and said carbidopa compound constitute together 50% by weight of said formulation.

9. The method according to claim 1, wherein said neurological disease is Parkinson’s disease.

10. The method according to claim 1, using a controller in communication with said pump to control operation of said pump, and using a sensor which is in communication with said controller to sense if said formulation contacts tissue in a peritoneal cavity outside a duodenum of said gastrointestinal tract.

11. The method according to claim 10, comprising stopping operation of said pump if said sensor senses that the formulation contacts tissue in the peritoneal cavity outside the duodenum.

12. A method of making a formulation comprising a levodopa compound and a carbidopa compound, comprising: dissolving a powder comprising a levodopa compound and a carbidopa compound in acidic water to form a solution; performing sonication or vortexing, freezing, and lyophilization or grinding or milling, of said solution to form a substance; and performing reconstitution of said substance in a reconstitution matrix to form a formulation, wherein the levodopa compound and the carbidopa compound are at least 30% by weight of said formulation.

13. The method according to claim 12, wherein sonication and vortexing of said solution are done.

14. The method according to claim 12, wherein a viscosity of said formulation is not greater than 50 centipoise at 37° C.

15. The method according to claim 12, wherein a viscosity of said formulation is in a range of 1-50 centipoise at 25° C.

16. The method according to claim 12, wherein a ratio between the levodopa compound and the carbidopa compound is in a range of 3.5:1 - 10: 1.

17. The method according to claim 12, wherein said levodopa compound is in a range of 300-1000 mg/ml and said carbidopa compound is in a range of 75-300 mg/ml.

18. The method according to claim 13, wherein said matrix comprises water, acidic water with a pH in a range of 1-3, polyethylene glycol or polyvinylpyrrolidone.

19. The method according to claim 1, wherein said levodopa compound comprises levodopa, or levodopa salts or levodopa ester including ethyl or propyl isopropyl esters, or other levodopa products, and said carbidopa compound comprises carbidopa, or carbidopa ester including carbidopa propyl ester or carbidopa isopropyl ester.

20. The method according to claim 1, wherein said formulation comprises benserazide or other dopa decarboxylase inhibitor.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which:

[0027] FIG. 1 is a simplified illustration of a device that is implanted subcutaneously and which delivers a substance into the gastrointestinal (GI) tract, constructed and operative in accordance with a non-limiting embodiment of the present invention; and

[0028] FIG. 2 is a simplified illustration of the device of FIG. 1.

DETAILED DESCRIPTION OF EMBODIMENTS

[0029] Reference is now made to FIG. 1, which illustrates a device 10, constructed and operative in accordance with a non-limiting embodiment of the present invention, subcutaneously implanted in a patient.

[0030] FIG. 1 illustrates a portion of the gastrointestinal (GI) tract, including the esophagus 1, stomach 2, and duodenum 3 (proximal portion of the small intestine). The pyloric part 4 of the stomach leads to the duodenum 3 by way of the pylorus 5.

[0031] Reference is now made to FIG. 2. The device 10 includes a reservoir 12 for storing therein a formulation (substance) 14 for delivery to the GI tract 3. The amount of formulation 14 contained in reservoir 12, may be sufficient for continuous delivery of at least 24 hours, or alternatively several days or alternatively other time periods.

[0032] The device 10 is implanted under the skin (subcutaneously) and it includes a pump 16 for pumping substance 14 from reservoir 12 via a cannula 18 into the GI tract 3.

[0033] In one embodiment, the formulation 14 contains high concentrations of levodopa and carbidopa or levodopa ester and carbidopa ester, or other products of levodopa and carbidopa, together with a compound that enhances the absorption of the levodopa/carbidopa compounds into the GI tract; yet the formulation has sufficiently low viscosity so that the formulation can be delivered over long periods of time with the subcutaneously implanted pump and cannula, without the pump being overworked and without the cannula becoming clogged.

[0034] For example, without limitation, the ratio between the levodopa compound and the carbidopa compound is generally 4:1; levodopa compound (e.g. levodopa, or levodopa ester) is in the range of 300-1000 mg/ml and carbidopa compound (carbidopa, or carbidopa ester) is in the range of 75-300 mg/ml. The formulation may also contain an intestinal absorbance enhancer, such as, but not limited to, chitosan, to enhance the absorbance of the active drugs via the GI tract. The viscosity of the formulation that contains all the ingredients, including levodopa-carbidopa substance is in the range of 1-50 centipoise.

[0035] Without limitation, in one example, substance 14 may include several levodopa esters, including the ethyl ester, propyl ester, isopropyl ester and butyl ester. In experiments, these esters were successfully dissolved in water to which was added acetic acid until attaining pH 5 (in some cases pH 4.5). The ethyl ester had the highest solubility, but the propyl and the isopropyl esters were also soluble at a concentration of 400 mg/ml. The propyl ester of carbidopa was solubilized under the same conditions and a clear solution of 100 mg/ml of the carbidopa propyl ester was obtained. A mixture of each of the above levodopa esters with carbidopa propyl ester was prepared at a ratio of 4:1 (levodopa ester/carbidopa ester) and a clear solution was obtained. The solution of the mixture was stable for at least two weeks based on chromatographic determination of levodopa esters and carbidopa ester. The formulations of the levodopa esters together with carbidopa ester were prepared in diluted acetic acid and ascorbic acid at a pH 5. Each one of the above mentioned esters have good stability.

[0036] Accordingly, levodopa and carbidopa formulations are stabilized using pH 4.5-5. The levodopa and carbidopa esters can be administered into the GI tract over extended periods by pump 16.

[0037] Pump 16 may be, without limitation, a diaphragm pump, peristaltic pump, motor-driven pump or any other suitable pump. Pump 16 may be controlled by a controller 20, which may be part of device 10, or alternatively, may be external and communicates wirelessly with pump 16. A battery 22 may be provided in device 10 for powering the pump and controller and any other electrical components of device 10.

[0038] The cannula 18 may have a spike or other end for entering the GI tract 3. The point of entry may be at any suitable portion of the GI tract 3, such as but not limited to, the stomach, any portion of the duodenum, or near the proximal part of the jejunum.

[0039] Alternatively, as seen in FIG. 1, device 10 may be implanted subcutaneously and cannula 18 may pass through the stomach wall, and then placed in the stomach near the pylorus, or pass through the pylorus to the duodenum, or proximal jejunum.

[0040] The device 10 may include a port 24 communicating with reservoir 12 and accessible from outside the skin, such as by a syringe 26. Port 24 may be used to refill reservoir 12 with substance 14. Additionally, port 24 (or another dedicated port) may be used to access cannula 18 for draining and washing cannula 18 (with saline or water, for example).

[0041] Device 10 may be anchored to the skin with sutures, barbs and other fixation devices 28, without causing trauma or discomfort to the patient. Device 10 may also include a cannula fixation device 32 for anchoring cannula 18 to the duodenum and for sealing cannula 18 to the duodenum.

[0042] Contact between the formulation 14 and tissues in the peritoneal cavity should be avoided. In accordance with a non-limiting embodiment of the present invention, device 10 includes one or more sensors 30 that sense if the formulation 14 contacts tissue in the peritoneal cavity outside the duodenum. Alternatively, sensor 30 may sense the flow of the formulation from the reservoir into the duodenum during the period of the pump activity. In case the formulation does not reach the duodenum in a suitable rate, the action of the pump will be stopped. Accordingly, sensor 30 may be a chemical sensor, fluid sensor, capacitance sensor, and others. Sensor 30 is in communication with controller 20. Upon sensing contact of the formulation 14 with tissue in the peritoneal cavity, controller 20 stops operation of pump 16.

[0043] The following describes examples of preparation of a substance for subcutaneous delivery, the substance containing a high concentration of levodopa and carbidopa.

Example 1

[0044] The substance is in powder form. 3.7185 g powder consists of: 1.48 g Levodopa and 0.370 g Carbidopa, which means a total of 1.85 g API (active pharmaceutical ingredient) =47% of the powder is the API. The remainder of the powder consists of 1.85 g random methyl-β-cyclodextrin and 0.0185 g anti-oxidant. Examples of anti-oxidants include, without limitation, ascorbic acid, ascorbyl palmitate, and tocopherol succinate.

[0045] The powder underwent dissolution in a large volume of acidic water. Examples of acidic water include, without limitation, solutions of phosphoric acid (H.sub.3PO.sub.4) or hydrochloric acid (HCl).

[0046] The solution then underwent vortexing and sonication, followed by freezing and lyophilization. It is noted that the invention includes just sonication, just vortexing or a combination of both. The sonication may be done, without limitation, ultrasonically at 40 KHz. Alternatively, instead of lyophilization, the substance may undergo grinding or milling, such as jet milling. Afterwards, the substance was reconstituted in a 1 g reconstitution matrix to arrive at the final formulation. The matrix was selected from acidic water (pH=1.5), polyethylene glycol 400 or polyvinylpyrrolidone (PVP).

[00001]$\begin{array}{l}\text{The}\text{resultant}\text{weight}\text{of}\text{the}\text{solution}=\\ \text{3}{\text{.7185}}_{\text{powder}}{\text{+1}}_{\text{matrix}}\text{=}4.7185\text{g}\end{array}$

[00002]$\begin{array}{l}\%\text{API}{}_{\text{w}/\text{w}}\text{=}\\ \text{1}{\text{.85}}_{\text{APIweight}}/\left(\text{3}{\text{.7185}}_{\text{powder}\text{weight}}{\text{+1}}_{\text{matrix}\text{weight}}\right)\times \\ 100=39.21\%\text{w}/\text{w}\end{array}$

[00003]$\begin{array}{l}\%{\text{API}}_{\text{w}/\text{v}}=\text{\%API}{}_{\text{w}/\text{w}}\text{X}\text{sample}\text{density}\text{=39}\text{.21}\times \text{1}\text{.2}=\\ \text{47\%}{}_{\text{w}/\text{v}}\text{=}470.5\text{mg}/\text{ml}\end{array}$

[00004]$\text{Sample}\text{density}=\text{1}\text{.2g}/\text{ml}$

Example 2

[0047] 3.5 ml of 0.2 N HCl were added to 200 mg of L- DOPA, 50 mg of carbidopa and 2.5 mg of ascorbic acid and the mixture was vortexed and then sonicated. Under these conditions L- DOPA did not fully dissolve. Then 1N HCl was added dropwise till all L-DOPA was dissolved.

[0048] The procedure was repeated for a mixture of 200 mg of L- DOPA, 50 mg of carbidopa, 2.5 mg of ascorbic acid and 250 mg of hydroxypropyl-beta-cyclodextrin (HPβCD).

[0049] Each of the above solutions was lyophilized and reconstituted in 0.4 ml H.sub.2O to yield 0.5 ml solution. Each of the solutions was sonicated. Only the formulation that contained HPβCD was clear, while the formulation without HPβCD was very turbid as the L-DOPA/carbidopa did not dissolve.

[0050] The formulation that contained HPβCD contained 50% of the API weight per volume. The color of this clear solution of the formulation that contained HPβCD was pale yellowish and did not change under storage for at least two weeks.