Devices for evaporation and inhalation of active agents

Abstract

There is provided an inhalation device for delivering a deliverable agent in the form of an aerosol or vapour to a user. The device comprises a solid, porous carrier material having a defined porosity, and a deliverable agent located within the pores of the carrier material. The device is operable to heat the carrier material and vaporise the deliverable agent. Deliverable agents that may be delivered to the user include active pharmaceutical ingredients. Suitable materials for the porous carrier material include chemically bonded ceramic materials and geopolymeric materials.

Claims

1. A device for delivering a deliverable agent in the form of an aerosol or vapor to a user, the device comprising a solid, porous carrier material based on: (a) one or more chemically bonded ceramic materials, wherein the porous carrier material based on the one or more chemically bonded ceramic materials is not glass or (b) one or more geopolymeric materials, and having a porosity of at least 10%, and a deliverable agent located within the pores of the carrier material, wherein the device is operable to heat the carrier material and vaporize the deliverable agent, wherein the deliverable agent is an active pharmaceutical ingredient that is not nicotine or a salt thereof.

2. The device according to claim 1, wherein the solid, porous carrier material has a porosity of from about 20% to about 70%.

3. The device according to claim 1, wherein the average pore size in the carrier material is from about 0.1 μm to about 500 μm.

4. The device according to claim 1, wherein the deliverable agent is located predominantly within the pores of the carrier material.

5. The device according to claim 1, wherein the carrier material is selected from the list consisting of: (i) a material obtainable by the process of reacting an aluminosilicate precursor material with an aqueous alkaline liquid; and (ii) a calcium phosphate, a calcium sulfate, a calcium carbonate, a calcium silicate, a calcium aluminate, a magnesium carbonate, an aluminium silicate, and combinations thereof.

6. The device according to claim 1, wherein the carrier material is (i) a ceramic selected from the group consisting of, calcium sulfate,calcium phosphate, calcium silicate, calcium carbonate, calcium aluminate, magnesium carbonate, or a combination thereof, or (ii) a material obtainable by the process of reacting an aluminosilicate precursor material selected from the group consisting of kaolin, dickite, halloysite, nacrite, zeolites, illite, dehydroxylated zeolite, dehydroxylated halloysite, and metakaolin with an aqueous alkaline liquid.

7. The device according to claim 1, wherein the active pharmaceutical ingredient is an opioid analgesic or a non-steroidal anti-inflammatory drug (NSAID).

8. The device according to claim 7, wherein (a) the opioid analgesic is selected from morphine, oxycodone, buprenorphine, alfentanil, sufentanil, remifentanil and fentanyl or (b) the NSAID is selected from the group consisting of ibuprofen and aspirin.

9. The device according to claim 1, wherein the carrier material and the deliverable agent are provided together in a replaceable cartridge.

10. The device according to claim 9, wherein the replaceable cartridge consists essentially of the carrier material and the deliverable agent.

11. The device according to claim 1, further comprising a heating element operable to heat the carrier material.

12. The device according to claim 11, wherein the heating element is located proximally to the carrier material.

13. The device according to claim 1, wherein the device comprises a sufficient quantity of the active pharmaceutical ingredient to provide no more than one unit dosage of the active pharmaceutical ingredient to the user.

14. A method of delivering a deliverable agent in the form of a vapor or aerosol to a user, which method comprises: (a) providing a device comprising: (i) a solid, porous carrier material having a porosity of at least 10%; and (ii) a deliverable agent, wherein the deliverable agent is located within the pores of the carrier material and wherein the device is operable to heat the carrier material and vaporize the deliverable agent; and (b) heating the carrier material to vaporize the deliverable agent, wherein the carrier material is based on one or more chemically bonded ceramic materials or one or more geopolymeric materials, wherein the porous carrier material based on the one or more chemically bonded ceramic materials is not glass, and wherein the deliverable agent is an active pharmaceutical ingredient that is not nicotine or a salt thereof.

Description

(1) The invention is illustrated by the following examples in which:

(2) FIG. 1 shows the amount of ibuprofen in ceramic discs before (control) and after heat treatment (AH; n=1). Error bars show the maximum and minimum values;

(3) FIG. 2 shows the amount of nicotine in ceramic discs before (control; n=1) and after heat treatment (AH; n=2). Error bars show the maximum and minimum values;

(4) FIG. 3 shows the amount of nicotine in aluminium oxide rods before and after oven heat treatment (n=3);

(5) FIG. 4 shows the amount of nicotine in calcium sulphate rods before and after oven heat treatment (n=3);

(6) FIG. 5 shows the amount of nicotine in calcium sulphate coins before and after oven heat treatment (n=3);

(7) FIG. 6 shows the amount of nicotine in geopolymer coins before and after oven heat treatment (n=3);

(8) FIG. 7 shows the experimental setup for the e-cigarette device;

(9) FIG. 8 shows the amount of nicotine in calcium sulphate rods before and after heat treatment in an e-cigarette device (n=3);

(10) FIG. 9 shows the amount of nicotine in aluminium oxide rods before and after heat treatment in an e-cigarette device (n=3);

(11) FIG. 10 shows the experimental setup for the induction tests;

(12) FIG. 11 shows the amount of nicotine in calcium sulphate coins before and after heat treatment using induction heating (n=3); and

(13) FIG. 12 shows the amount of nicotine in calcium sulphate coins before and after heat treatment using induction heating on a pre-heated plate (n=3);

(14) FIG. 13 shows the amount of sumatriptan succinate in Al.sub.2O.sub.3 rods before and after heat treatment using oven heating;

(15) FIG. 14 shows the amount of clonidine hydrochloride in calcium sulphate coins before and after oven heat treatment (n=2);

(16) FIG. 15 shows the amount of clonidine hydrochloride in calcium sulphate coins before and after oven heat treatment (n=2);

(17) FIG. 16 shows the amount of nicotine in calcium sulphate coins before and after oven heat treatment (n=2); and

(18) FIG. 17 shows the amount of sumatriptan succinate in calcium sulphate coins before and after oven heat treatment (n=2).

EXAMPLES

Example 1

Oven Heating

(19) Ceramic discs comprising ibuprofen (IOL Chemicals and Pharmaceuticals Ltd, India) were prepared using aluminium oxide (Al.sub.2O.sub.3; Keranova, Sweden) as follows.

(20) Ceramic discs (Al.sub.2O.sub.3) with different pore sizes (0.25, 1, 6, 15 and 30 μm) were prepared in two sizes: (i) 63 mm in diameter and 6.3 mm in thickness (pore sizes 0.25, 1 and 6 μm); and (ii) 48 mm in diameter and 6.3 mm in thickness (pore sizes 15 and 30 μm). The porosity was approximately 40% vol and the density 3.75 g/cm.sup.3 for all discs according to product specification.

(21) The discs (pore sizes 0.25, 1, 6, 15 and 30 μm) were soaked in a 400 ml in phosphate buffer with pH 7.4 (one phosphate buffer saline tablet (Sigma-Aldrich, USA) dissolved in 200 ml deionized water) with a concentration of 408.5 μg/ml ibuprofen for 24 hours. The discs were dried in room temperature for 24 hours. The discs were heated in an oven at 250° C. for 15 minutes, the control discs were not heated. All discs were measured for concentration of ibuprofen in 400 ml phosphate buffer pH 7.4 at 37° C. (USP paddle method (paddle speed 50 rpm), VanKel 7025, Varian Inc, USA) and the concentration for ibuprofen was measured using a UV spectrophotometer Shimadzu 1800, Japan at a wavelength of 220 nm to determine the amount of ibuprofen in the ceramic discs. The amount of ibuprofen in control discs was measured after 15 hours (i.e. after maximum drug release) and in heat treated discs after 1.5 hours (i.e. the maximal amount drug was at this time point released).

(22) The amount of ibuprofen remaining after heat treatment was zero for all samples. No significant changes in absorbance at other wavelengths were detected, indicating that no significant degradation of the ibuprofen had occurred.

Example 2

Oven Heating

(23) Ceramic discs comprising nicotine (nicotine solution (24 mg/ml), Ritch Group Ltd, United Kingdom) were prepared using aluminium oxide (Al.sub.2O.sub.3; Keranova, Sweden) as follows.

(24) Ceramic discs (Al.sub.2O.sub.3) with different pore sizes (0.25, 1, 6, 15 and 30 μm) were prepared in two sizes: (i) 63 mm in diameter and 6.3 mm in thickness (pore sizes 0.25, 1 and 6 μm); and (ii) 48 mm in diameter and 6.3 mm in thickness (pore sizes 15 and 30 μm). The porosity was approximately 40% vol and the density 3.75 g/cm.sup.3 for all discs according to product specification.

(25) A nicotine solution (0.25 ml; corresponding to 6 mg nicotine) was dispensed on the surface of the ceramic discs (pore sizes 0.25, 6, 15 and 30 μm). The discs were dried in room temperature for 24 hours. The discs were heated in an oven at 188° C. for 15 minutes, the control discs were not heated. All discs were measured for amount of nicotine in 400 ml phosphate buffer pH 7.4 at 37° C. (USP paddle method (paddle speed 50 rpm), VanKel 7025, Varian Inc, USA) and the concentration for nicotine was measured using a UV spectrophotometer Shimadzu 1800, Japan at a wavelength of 252.8 nm to determine the amount of nicotine in the ceramic discs. The amount of nicotine in control discs was measured after 15 hours (i.e. after maximum nicotine release) and in heat treated discs after 1.5 hours (i.e. the maximal amount nicotine was at this time point released).

(26) The amount of nicotine remaining after heat treatment very significantly reduced for all samples compared to the pre-heat treatment control samples. No significant changes in absorbance at other wavelengths were detected, indicating that no significant degradation of the nicotine had occurred.

Example 3

Oven Heating

(27) Aluminium Oxide Rods

(28) Aluminium oxide ceramic rods were obtained from Ceramtech (Sweden): Al.sub.2O.sub.3 cylindrical rods, 3 mm diameter and 10 mm length containing 4 bore holes (oriented axially) having a diameter of 0.8 mm.

(29) Calcium Sulphate Rods and Coins

(30) Calcium sulphate alpha hemihydrate (CaS) rods were obtained from Bo Ehrlander AB (Sweden). Shaped silicon rubbers were used as molds for both rods (diameter: 6, length 12 mm) and coins (diameter: 12 mm, thickness: 2 mm). The calcium sulphate was mixed with deionised water (Liquid/Powder ratio of 0.4 (w/w)) to form a homogenous paste, which was filled in the rubber molds. When the paste was applied, the molds were set to dry for at least 12 h under ambient conditions.

(31) Geopolymer Coins

(32) Reagent grade kaolinite, fumed silica (7 nm particle size) and reagent grade sodium hydroxide were obtained from Sigma-Aldrich (Sweden). Sodium silicate solution was manufactured by dissolving sodium hydroxide (NaOH) and fumed silica (SiO.sub.2) into deionised water. Metakaolin was formed by heating kaolinite for 2 hours in 800° C.

(33) Geopolymer were synthesized by mixing sodium silicate solution with metakaolin using mortar and pestle until a uniform paste was formed. The composition of the geopolymer obtained the following molar ratios: Si/Al=1.94, H.sub.2O/Al.sub.2O.sub.3=12.24 and Na.sub.2/Al.sub.2O.sub.3=1.23. The paste was filled into coin shaped silicon rubber molds and hardened in 100% humidity for 48 hours at ambient pressure at 37° C. After curing, geopolymer were dried at ambient temperature and humidity for 24 hours.

(34) Nicotine

(35) Pure nicotine USP/EP was obtained from BGP Healthcare pvt. Ltd. (India). E-juice (LIQUA) 18 mg/ml and 24 mg/ml were obtained from Cigoteket (Sweden). E-juice is a solution of nicotine dissolved in propylene glycol. Concentrations below 18 mg/ml were achieved by adding an appropriate amount of deionised water to the e-juice.

(36) Application of Nicotine

(37) The application of nicotine was achieved by either soaking or dispensing nicotine or a nicotine solution in a range of concentrations onto the surface of the ceramic rod/coin.

(38) Dispensing of Nicotine

(39) Pure nicotine (in liquid form), pure E-juice or E-juice diluted with water was dispensed onto the surface of the rods or coins. After application of nicotine, the samples were dried for 24 hours in room temperature before heat treatment and/or analysis.

(40) (ii) Soaking of Nicotine

(41) The rods were soaked in pure nicotine or a nicotine solution (exact volume was not measured, but the rod was just covered with liquid, about 100 μl). The samples were soaked for 24 hours in room temperature and thereafter the samples were dried for 24 hours, before heat treatment and/or analysis.

(42) Heating Method

(43) Oven Wilfa EMK 218 was obtained from Wilfa, (Norway). The temperature was set to approximately 200° C. The temperature was measured using an IR-thermometer from Mastech.

(44) Nicotine Release Detection

(45) All nicotine release tests were carried out according to the same analytical method. The sample was immersed into a beaker containing 50 ml of deionised water. After 24 hours a sample was taken out and filtered (pore size: 0.2 μm). The sample was characterized by UV-spectrophotometer at a wavelength of 219 nm. The amount nicotine in the samples were then calculated. The difference in amounts in the reference sample and the heat treated sample was estimated to have evaporated.

(46) The reference samples represent the amount of nicotine that was loaded before heat treatment. The difference in amount of nicotine detected in the heat-treated samples and the reference sample represents the amount of nicotine that evaporated during the heat treatment.

(47) Results—Aluminium Oxide

(48) Aluminium oxide rods were soaked in 6 mg/ml of nicotine solution (diluted e-juice) for 24 hours. The amount of nicotine remaining in the rods after before and heat treatment was measured, and is shown in FIG. 3.

(49) When heated, almost all of the nicotine was released within the first 5-10 min, since the amount of nicotine remaining in the samples after heat treatment was low. The rods were able to absorb approximately 135 μg nicotine/rod.

(50) Results—Calcium Sulphate

(51) Calcium sulphate rods were soaked in pure nicotine for 24 hours. The rods were able to absorb approximately 20 mg nicotine/rod. The amount of nicotine remaining in the rods after before and heat treatment was measured, and is shown in FIG. 4.

(52) Most of the nicotine was released during heating. It was observed that a higher amount was released during 5 min of heating compared to 1 min of heating.

(53) Pure nicotine (20 mg) was dispensed onto calcium sulphate coins. The amount of nicotine remaining in the coins after before and heat treatment was measured, and is shown in FIG. 5.

(54) Nicotine is a volatile substance and therefore the amount of nicotine detected in the reference sample was lower than 20 mg. Also in this case a lower release of nicotine was detected after heating.

(55) Results—Geopolymer

(56) Pure nicotine (20 mg) was dispensed onto geopolymer coins. The amount of nicotine remaining in the coins after before and heat treatment was measured, and is shown in FIG. 6.

(57) Nicotine is a volatile substance and therefore the amount of nicotine detected in the reference sample (about 16 mg) was less than that originally applied. Also in this case a lower release of nicotine was detected after heating.

Example 4

Heat Treatment Using an E-Cigarette Device

(58) Materials

(59) Aluminium oxide ceramic rods and calcium sulphate rods were obtained as described in Example 3. Nicotine and nicotine solutions were supplied and applied, and nicotine levels were detected as described in Example 3.

(60) Heating Apparatus

(61) Samples were heated using a prototype e-cigarette device (X-Cube II, Smoke) obtained from Devex Mekatronik AB (Sweden). The device is derived from the commercially available e-cigarette X-Cube.

(62) Method

(63) The sample in the device was heated up by a coil that is wrapped around the sample. The setting for the e-cigarette are listed in the table below.

(64) TABLE-US-00001 TABLE Settings for e-cigarette device Setting for E-cigarette Maximum temperature 315° C. Maximum power 6 W Coil Nickel

(65) The end of the device was connected to a vial via a silicon hose. The vial contained 1 ml of deionised water. To simulate smoking a rod was put into the device and puffing was performed. Puffing involves a sequence of 5 puffs that are each 10 seconds long. After puffing, the hose was removed and flushed with the water. The water was analysed for concentration of nicotine.

(66) Results—Calcium Sulphate

(67) Calcium sulphate rods were soaked for 24 hours in pure nicotine and heated (5*10 sec.) in the e-cigarette device. The amount of nicotine remaining in the rods after before and heat treatment was measured, and is shown in FIG. 8.

(68) The results show that a heat treatment in the device will result in a nicotine release.

(69) Results—Aluminium Oxide

(70) Aluminium oxide (Al.sub.2O.sub.3) rods were soaked for 24 hours in nicotine solution (18 mg/ml) and heated (5*10 sec.) in the device. The amount of nicotine remaining in the rods after before and heat treatment was measured, and is shown in FIG. 9.

Example 5

Heat Treatment Using Induction Heating

(71) Materials

(72) Calcium sulphate coins were obtained as described in Example 3. For the indirect induction test a magnet was molded into the coin. Nicotine and nicotine solutions were supplied and applied, and nicotine levels were detected as described in Example 3.

(73) Heating Apparatus

(74) Metal plate for induction cooker was obtained from Haneström (Sweden). Induction cooker Wilfa ICP-2000 was obtained from Media Markt (Sweden). Magnets (10*1 mm, Samarium Cobalt magnets, 0.4 kg pull) were obtained from first4magnets (UK). IR-thermometer (MS6520A) was obtained from Mastech (USA).

(75) Heating Method

(76) Heat treatment by indirect induction was carried out by placing a metal plate onto the induction cooker. The ceramic coins containing a magnet was applied onto the metal plate and heated on maximum effect (exact temperature was not measured; see FIG. 10).

(77) Results—Unheated Plate

(78) Nicotine solution (50μl, 18 mg/ml) was dispensed onto calcium sulphate coins and heated on an induction plate for about 1 minute or about 5 minutes. The amount of nicotine remaining in the coins after before and heat treatment was measured, and is shown in FIG. 11. Most of the nicotine was released within the first minute.

(79) Results—Pre-Heated Plate

(80) Nicotine solution (50μl, 18 mg/ml) was dispensed onto calcium sulphate coins. The plate was preheated for approximately 10 seconds in order to obtain a high temperature (at least 150° C.). The coins were heated for 5 seconds on the plate before being taken off. The coins were set to cool down for approximately 15 minutes before putting into the extraction bath. The amount of nicotine remaining in the coins after before and heat treatment was measured, and is shown in FIG. 12.

(81) The measurements show that a substantial quantity of nicotine was released as a result of the heat treatment.

Example 6

Sumatriptan Succinate

(82) Materials

(83) Aluminium oxide ceramic rods were obtained from Ceramtech (Sweden): Al.sub.2O.sub.3 cylindrical rods, 3 mm diameter and 10 mm length containing 4 bore holes (oriented axially) having a diameter of 0.8 mm. Sumatriptan succinate was obtained from SMS Pharmaceuticals Limited, India.

(84) Application of Sumatriptan Succinate

(85) The application of sumatriptan succinate was achieved by soaking the Al.sub.2O.sub.3 rods in a sumatriptan succinate solution with a concentration of 20 mg/ml. The volume of solution was around 100 μl but was not measured precisely; the volume was sufficient to fully immerse the rods. The samples were soaked for 24 hours in room temperature and thereafter the samples were dried for 24 hours, before heat treatment and/or analysis.

(86) Heating Apparatus and Method

(87) Oven Wilfa EMK 218 was obtained from Wilfa, (Norway). The temperature was set to approximately 300° C. The temperature was measured using an IR-thermometer from Mastech, USA. The rods were heated in the oven for a period of time ranging from 0 to 15 minutes.

(88) Sumatriptan Succinate Detection

(89) All sumatriptan release tests were carried out according to the same analytical method. The rods were immersed in a beaker containing 50 ml of deionised water. After 24 hours a sample of the water was taken out and filtered (pore size: 0.2 μm). The sample was characterized by UV-spectrophotometry at a wavelength of 282 nm. The amount sumatriptan succinate in the samples was then calculated. The reference samples represent the amount of sumatriptan succinate that was loaded before heat treatment. The difference between the amount of sumatriptan succinate detected in the heat-treated samples and the reference sample represents the amount of sumatriptan succinate that evaporated during the heat treatment.

(90) Results

(91) The amount of sumatriptan succinate remaining in the rods before and after heat treatment was measured, and is shown in FIG. 13.

(92) When heated, almost all of the sumatriptan succinate was released within the first 5-15 minutes, since the amount of sumatriptan succinate remaining in the samples after heat treatment was low. The rods were able to absorb approximately 1 mg sumatriptan succinate/rod.

Example 7

Heating of Calcium Sulfate Coins Pre-Loaded with Clonidine Hydrochloride

(93) Sample Preparation

(94) Calcium sulphate alpha hemihydrate (CaS) was obtained from Bo Ehrlander AB (Sweden). Clonidine hydrochloride was obtained from PCAS (Finland). Shaped silicon rubbers were used as molds for coins (diameter: 12 mm, thickness: 2 mm). The calcium sulphate was mixed with powder of Clonidine hydrochloride (0.07 g Clonidine hydrochloride/g calcium sulphate) and deionised water (Liquid/Powder ratio of 0.4 (w/w)) to form a homogenous paste, which was used to fill the rubber molds. Once the paste had been applied, the molds were set to dry for at least 12 h under ambient conditions.

(95) Heating Method

(96) Oven Wilfa EMK 218 was obtained from Wilfa (Norway). The oven temperature was set to approximately 250° C. The temperature was measured using an IR-thermometer from Mastech (USA). The coins were heated in the oven for a period of time ranging from 0 to 15 minutes.

(97) Clonidine Hydrochloride Release Detection

(98) Each coin was weighed and immersed into a beaker containing 200 ml of deionised water. After 24 hours a sample of liquid was taken out and filtered (pore size: 0.2 μm). The sample was characterized by Shimadzu LC-2030 (Germany) HPLC system with a Genesis C18 analytical column 4 μm (100×2.1 mm i.d.) with a mobile phase of acetonitrile/phosphoric acid, pH 3 (11/89). The wavelength was set to 220 nm.

(99) The reference samples represent the amount of clonidine hydrochloride mg/g calcium sulphate that was loaded before heat treatment. The difference in amount of clonidine hydrochloride detected in the heat-treated samples and the reference sample represents the amount of clonidine hydrochloride that evaporated during the heat treatment.

(100) Results—Calcium Sulphate

(101) Clonidine hydrochloride was mixed together with calcium sulphate (0.07 g clonidine hydrochloride/g Calcium sulphate) to form coins. The coins contained approximately 17 mg clonidine hydrochloride (1 coin weighed approximately 0.3 g). The coins were heated as described above (or not heated, in the case of the reference sample). The amount of clonidine hydrochloride remaining in the coins before and after heat treatment was measured, and is shown in FIG. 14. When heated, almost all of the clonidine hydrochloride was released within the first 15 mins, since the amount of clonidine hydrochloride remaining in the samples after heat treatment was low.

Example 8

Heating Calcium Sulfate Coins Loaded with Clonidine Hydrochloride

(102) Sample Preparation

(103) Calcium sulphate alpha hemihydrate (CaS) was obtained from Bo Ehrlander AB (Sweden). Clonidine hydrochloride was obtained from PCAS (Finland). Shaped silicon rubbers were used as molds for coins (diameter: 12 mm, thickness: 2 mm). The calcium sulphate was mixed with deionised water (Liquid/Powder ratio of 0.4 (w/w)) to form a homogenous paste, which was used to fill the rubber molds. When the paste was applied, the molds were set to dry for at least 12 h under ambient conditions.

(104) Clonidine hydrochloride solution (50 μl, 5 mg/ml) was dispensed onto the calcium sulphate coins. When the solution was applied, the coins were set to dry for at least 12 h under ambient conditions.

(105) Heating Method

(106) Oven Wilfa EMK 218 was obtained from Wilfa, (Norway). The temperature was set to approximately 250° C. The temperature was measured using an IR-thermometer from Mastech, (USA). The coins were heated in the oven for a period of time ranging from 0 to 15 minutes.

(107) Clonidine Hydrochloride Release Detection

(108) Each coin was weighed and immersed into a beaker containing 200 ml of deionised water. After 24 hours a sample of the water was taken out and filtered (pore size: 0.2 μm). The sample was characterized by Shimadzu LC-2030 (Germany) HPLC system with a Genesis C18 analytical column 4 μm (100×2.1 mm i.d.) with a mobile phase of acetonitrile/phosphoric acid, pH 3 (11/89). The wavelength was set to 220 nm.

(109) The reference samples represent the amount of clonidine hydrochloride that was loaded before heat treatment. The difference in amount of clonidine hydrochloride detected in the heat-treated samples and the reference sample represents the amount of clonidine hydrochloride that evaporated during the heat treatment.

(110) Results—Calcium Sulphate

(111) Clonidine hydrochloride solution (50 μl, 5 mg/ml) was dispensed onto the calcium sulphate coins. The coins were heated as described above (or not heated, in the case of the reference sample). The amount of clonidine hydrochloride remaining in the coins before and after heat treatment was measured, and is shown in FIG. 15. During heating, the amount of clonidine hydrochloride present in the coins decreased significantly over time.

Example 9

Heating of Calcium Sulfate Coins Pre-Loaded with Nicotine

(112) Sample Preparation

(113) Calcium sulphate alpha hemihydrate (CaS) was obtained from Bo Ehrlander AB (Sweden). Shaped silicon rubbers were used as molds for coins (diameter: 12 mm, thickness: 2 mm). The calcium sulphate was mixed with a nicotine solution with a concentration of 5 or 20 mg/ml of nicotine (Liquid/Powder ratio of 0.4 (w/w)) to form a homogenous paste, which was filled in the rubber molds. Once the paste was applied, the molds were set to dry for at least 12 h under ambient conditions.

(114) Heating Method

(115) Oven Wilfa EMK 218 was obtained from Wilfa, (Norway). The temperature was set to approximately 200° C. The temperature was measured using an IR-thermometer from Mastech, (USA). The coins were heated in the oven for a period of time ranging from 0 to 15 minutes.

(116) Nicotine Release Detection

(117) Each coin was immersed into a beaker containing 50 ml of deionised water. After 24 hours a sample was taken out and filtered (pore size: 0.2 μm). The sample was characterized by UV-spectrophotometer at a wavelength of 219 nm. The amount nicotine in the samples were then calculated. The difference in amounts in the reference sample and the heat treated sample represents the amount of nicotine that evaporated during the heat treatment.

(118) The reference samples represent the amount of nicotine μg/g calcium sulphate that was loaded before heat treatment. The difference in amount of nicotine detected in the heat-treated samples and the reference sample represents the amount of nicotine that evaporated during the heat treatment.

(119) Results

(120) Two different nicotine solutions were used to make coins; 5 mg/ml and 20 mg/ml. The same Liquid/Powder ratio of 0.4 (w/w) was used in both batches. The coins contained approximately 180 μg (for the coins mixed with 5 mg/ml nicotine solution) and 390 μg (for the coins mixed with 20 mg/ml nicotine solution). The amount of nicotine remaining in the coins before and after heat treatment was measured, and is shown in FIG. 16.

Example 10

Heating Calcium Sulfate Coins Pre-Loaded with Sumatriptan Succinate

(121) Sample Preparation

(122) Calcium sulphate alpha hemihydrate (CaS) was obtained from Bo Ehrlander AB (Sweden). Sumatriptan succinate was obtained from SMS Pharmaceuticals Limited, India. Shaped silicon rubbers were used as molds for coins (diameter: 12 mm, thickness: 2 mm). The calcium sulphate was mixed with sumatriptan succinate (0.07 g sumatriptan succinate/g calcium sulphate) and deionised water (Liquid/Powder ratio of 0.4 (w/w)) to form a homogenous paste, which was filled in the rubber molds. When the paste was applied, the molds were set to dry for at least 12 h under ambient conditions.

(123) Heating Method

(124) Oven Wilfa EMK 218 was obtained from Wilfa, (Norway). The temperature was set to approximately 250° C. The temperature was measured using an IR-thermometer from Mastech, (USA). The coins were heated in the oven for a period of time ranging from 0 to 15 minutes.

(125) Sumatriptan Succinate Detection

(126) The coins were immersed in a beaker containing 50 ml of deionised water. After 24 hours a sample of the water was taken out and filtered (pore size: 0.2 μm). The sample was characterized by UV-spectrophotometry at a wavelength of 282 nm. The amount Sumatriptan succinate in the samples was then calculated.

(127) The reference samples represent the amount of Sumatriptan succinate that was loaded before heat treatment. The difference between the amount of Sumatriptan succinate detected in the heat-treated samples and the reference sample represents the amount of Sumatriptan succinate that evaporated during the heat treatment.

(128) Results

(129) The amount of sumatriptan succinate remaining in the coins before and after heat treatment was measured, and is shown in FIG. 17. When heated, almost all of the Sumatriptan succinate was released within the first 15 mins, since the amount of Sumatriptan succinate remaining in the samples after heat treatment was low.