Compositions for buccal administration

Abstract

The present application provides compositions that are provided within a semi-permeable membrane. The compositions can include a particulate material, such as a cellulose, a sugar alcohol, and nicotine. The composition can provide a fast onset of action of the nicotine in the mouth of a user. In particular, when subjected to an in vitro dissolution test using UV detection, about 30% or more of the total content of the nicotine is released from the composition within 30 minutes.

Claims

1. A composition for buccal administration, the composition comprising: carrier particles; a sugar alcohol; and nicotine; wherein the carrier particles and the nicotine together comprise about 45% or greater by weight of the composition, based on the total weight of the composition; and wherein the composition is enclosed within a semi-permeable membrane.

2. The composition of claim 1, wherein the semi-permeable membrane is effective to substantially prevent release of the carrier particles without substantially preventing release of the nicotine.

3. The composition of claim 1, wherein semi-permeable membrane is configured as a pouch or bag.

4. The composition of claim 3, wherein the pouch or bag is formed at least partially of one or more of cellulose, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinyl acetate, polycarbonate, polyethylene terephthalate, polyester, polyamide, nylon, and polymers of methacrylates and acrylates.

5. The composition of claim 1, wherein the carrier particles are formed at least partially of a cellulose.

6. The composition of claim 1, wherein the carrier particles and the nicotine together comprise about 80% to about 98% by weight of the composition, based on the total weight of the composition.

7. The composition of claim 1, wherein the sugar alcohol is one or more of xylitol, sorbitol, maltitol, and isomalt.

8. The composition of claim 1, wherein the nicotine is a polacrilex.

9. The composition of claim 1, wherein the nicotine is one or more of nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride, and nicotine salicylate.

10. The composition of claim 1, further comprising a buffering agent.

11. The composition of claim 10, wherein the buffering agent is selected from the group consisting of acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, and mixtures thereof.

12. The composition of claim 10, wherein the buffering agent is a hydrogen carbonate.

13. The composition of claim 1, further comprising one or more artificial sweeteners.

14. The composition of claim 1, wherein when the composition is subjected to an in vitro dissolution test using UV detection, about 30% or more of the total content of the nicotine is released from the composition within 30 minutes.

15. A composition for buccal administration, the composition comprising: carrier particles; a sugar alcohol; and about 0.5 mg to about 10 mg of nicotine, calculated as a nicotine free base; wherein the carrier particles and the nicotine together comprise about 45% or greater by weight of the composition, based on the total weight of the composition; wherein the nicotine is present in a concentration of about 0.1% to about 10% by weight based on the total weight of the composition; and wherein the composition is enclosed within a semi-permeable membrane.

16. The composition of claim 15, wherein the semi-permeable membrane is effective to substantially prevent release of the carrier particles without substantially preventing release of the nicotine.

17. The composition of claim 15, wherein semi-permeable membrane is configured as a pouch or bag.

18. The composition of claim 17, wherein the pouch or bag is formed at least partially of one or more of cellulose, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinyl acetate, polycarbonate, polyethylene terephthalate, polyester, polyamide, nylon, and polymers of methacrylates and acrylates.

19. The composition of claim 15, wherein the carrier particles are formed at least partially of a cellulose.

20. The composition of claim 15, wherein the sugar alcohol is one or more of xylitol, sorbitol, maltitol, and isomalt.

21. The composition of claim 15, wherein the nicotine is a polacrilex.

22. The composition of claim 15, wherein the nicotine is one or more of nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride, and nicotine salicylate.

23. The composition of claim 15, further comprising a buffering agent.

24. The composition of claim 23, wherein the buffering agent is selected from the group consisting of acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, and mixtures thereof.

25. The composition of claim 23, wherein the buffering agent is a hydrogen carbonate.

26. The composition of claim 15, further comprising one or more artificial sweeteners.

27. The composition of claim 15, wherein the carrier particles and the nicotine together comprise about 80% to about 98% by weight of the composition, based on the total weight of the composition.

28. The composition of claim 15, wherein when the composition is subjected to an in vitro dissolution test using UV detection, about 30% or more of the total content of the nicotine is released from the composition within 30 minutes.

29. A composition for buccal administration, the composition comprising: particles of a cellulose; a sugar alcohol; a buffering agent is selected from the group consisting of acetates, glycinates, phosphates, glycerophosphates, citrates, carbonates, hydrogen carbonates, borates, and mixtures thereof; and about 0.5 mg to about 10 mg of nicotine, calculated as a nicotine free base; wherein the particles of the cellulose and the nicotine together comprise about 80% to about 98% by weight of the composition, based on the total weight of the composition; wherein the nicotine is present in a concentration of about 0.1% to about 10% by weight based on the total weight of the composition; wherein when the composition is subjected to an in vitro dissolution test using UV detection, about 30% or more of the total content of the nicotine is released from the composition within 30 minutes; and wherein the composition is enclosed within a semi-permeable membrane that is effective to substantially prevent release of the particles without substantially preventing release of the nicotine.

30. The composition of claim 29, wherein one or more of the following conditions is met: the semi-permeable membrane is formed at least partially of one or more of cellulose, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinyl acetate, polycarbonate, polyethylene terephthalate, polyester, polyamide, nylon, and polymers of methacrylates and acrylates; the sugar alcohol is one or more of xylitol, sorbitol, maltitol, and isomalt; the nicotine is one or more of nicotine base, nicotine hydrochloride, nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate, nicotine sulfate, nicotine zinc chloride, nicotine salicylate, and a polacrilex.

Description

LEGENDS TO THE FIGURES

(1) FIG. 1 shows an assembly of the dialysis membrane to the silicone hosethe assembly is a part of the dissolution testing apparatus for testing of snuff compositions

(2) FIG. 2 shows an overview of tubing routes in the dissolution testing of snuff compositions

(3) FIG. 3 shows a sample tube for dissolution testing of snuff compositions

(4) FIGS. 4 and 5 show in vitro release profile for snuff compositions described in Example 2

(5) FIGS. 6 and 7 show the in vivo uptake of nicotine from snuff compositions described in Example 3.

(6) FIG. 8 show the plasma concentration versus time for the experiment described in Example 5 comparing Nicorette chewing gum (4 mg) with a snuff composition of the invention containing 5 mg of nicotine

METHODS

(7) In vitro Dissolution Test

(8) The snuff compositions according to the invention are normally tested to fulfill specific requirements with respect to in vitro release of nicotine. A suitable in vitro test depends on the specific composition in question. In general, a person skilled in the art will find guidance as to how to choose a relevant dissolution test for a specific composition in the official monographs such as, e.g., the European Pharmacopoeia. Below are described suitable dissolution tests in case of snuff compositions.

(9) Snuff

(10) The following dissolution method for testing of the release of nicotine from snuff compositions was used.

(11) The method describes in-vitro release of nicotine from snuff using UV detection. The released nicotine diffuses through a dialysis membrane into a stream of tempered phosphate buffer.

(12) Equipment

(13) TABLE-US-00001 UV spectrophotometer HP 8453 or equivalent Sipper HP Peristaltic pump or equivalent Secondary pump Flexicon PF5 or equivalent Magnetic stirrer Labasco or equivalent Water bath Gant W14 or equivalent
Instrument Settings

(14) TABLE-US-00002 UV spectrophotometer Wavelengths 244, 259 and 274 nm Flow cell 1.000 cm Waterbath Temperature 37 C. Secondary pump Pump flow 30 rpm Magnetic stirrer Rotation Gentle stir
Materials Dialysis membrane, Spectra/Por, MWCO 500, Silicon tubing, i.d. 6 mm Sample tube 250 ml beaker Reagents Chemicals & Solvents: Purified water, H.sub.2O Sodium Hydroxide, min 98%, NaOH Sodium Dihydrogen Phosphate Monohydrate, min 98%, NaH.sub.2PO.sub.4H.sub.2O Reference Material: Nicotine bitartrate dihydrate, standard Solutions: 5 M Sodium hydroxide Phosphate buffer, pH 6.8 Procedure
Apparatus Assembly

(15) Cut two pieces of silicon hoses, 150 and 35 cm long. Insert a 3 cm long hard plastic hose (o.d. 7 mm) in one end of the two blood vessels for support. Cut a piece of dialysis membrane and pre-treat according to manufacturer. Thread the membrane through two 2.5 cm long silicon hose pieces (i.d. 6 mm). The supported ends of the blood vessels should be inserted approximately 3 cm into the membrane and secured with the two small silicon rings (See FIG. 1).

(16) Add 250 ml phosphate buffer [6] to the 250 ml beaker and add a magnetic bar. Place it in the water bath and start the heating and rotation. Connect the silicone hose to the secondary pump and place the longest part to the beaker. Place a pipette tip (1 ml) into the shorter end to work as a pressure restrictor. The hole in the tip may be expanded in order to adjust the back pressure. Prime the tubing with buffer.

(17) Place the two tubings from the flow cell in the beaker. (See FIG. 2) and obtain a blank measurement.

(18) Stop the flow and fold the membrane on the middle. Use a piece of paper to slide the membrane into the sample tube as far down as possible. Start the pump and carefully insert the snuff bag halfway down the sample tube between the membranes (see FIG. 3). Add phosphate buffer [2] to the tube enough to cover the sample. Place the sample tube in the water bath and start the analysis.

(19) Sampling

(20) Blank: Measure blank before the membrane is placed into the sample tube. Sampling: Withdraw sample online every fifth minute for 30 minutes using the sipper. Measure the absorbance at 244, 259 and 274 nm. Standards: Pump S1-S3 into the flow cell after the sampling sequence. Measure the absorbance at 244, 259 and 274 nm.
Evaluation

(21) The concentrations of nicotine in the samples are calculated.

(22) As an alternative method, USP basket method (in vitro dissolution of tablets) can be used employing 500 ml water as dissolution medium.

(23) The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

EXAMPLES

Example 1

(24) Snuff Bag Compositions E, F, G, H, I, and J

(25) Nicotine was sorbed onto microcrystalline cellulose (MCC) as described in WO 2004/056363. Accordingly, in the present example 2.40 ml nicotine was dissolved in 25 ml ethanol (99.5%). 47.6 g MCC of type PH-102 was loaded into a high-speed mixer and the nicotine was slowly added. After vacuum drying of the obtained wetted mass a fine-grained, white powder of nicotine-microcrystalline cellulose carrier complex was obtained.

(26) Nicotine was sorbed onto microcrystalline cellulose (MCC) to obtain nicotine-microcrystalline cellulose carrier complexes essentially as described above. The obtained nicotine-microcrystalline cellulose carrier complexes were mixed with the remaining ingredients to obtain the compositions E, F, G, H, I and J stated in the following table:

(27) TABLE-US-00003 COMPOSITION Compo- Compo- Compo- Compo- Compo- Compo- sition E sition F sition G sition H sition I sition J Quantity Quantity Quantity Quantity Quantity Quantity Ingredient (mg/unit) (mg/unit) (mg/unit) (mg/unit) (mg/unit) (mg/unit) Nicotine 6.00 6.00 6.00 4.00 4.00 6.00 Micro- 138 137 137 139 139 135 crystalline cellulose Peppermint 6.00 6.00 6.00 6.00 6.00 6.00 powder flavour Acesulfame 0.06 0.06 0.06 0.06 0.06 0.06 Aspartame 0.06 0.06 0.06 0.06 0.06 0.06 powder Sodium 1.20 carbonate Sodium 1.20 1.20 1.20 hydrogen carbonate Sodium 1.20 1.20 triphosphate Target 150 150 150 150 150 150 Weight Measured 9.47 9.02 10.4-10.8 8.95 10.3-10.5 9.95 pH, 5 g in 100 ml H2O In-vitro 2.6 2.6 2.6-2.7 1.8 1.6-1.7 3.0 release, 30 min (mg)* Measured 5.9 6.0 6.0-6.3 4.2 3.8-4.2 6.3 assay

(28) Nicotine was purchased from Siegfried, Switzerland, (batch no. 03381006), Microcrystalline cellulose was purchased from FMC, Belgium (batch no. M301C), Peppermint powder flavour was purchased from Firmenich, Switzerland (batch no. JP05040527), Acesulfame potassium was purchased from L&P Food Ingredient, China (batch no. (ZD02035), Aspartame powder was purchased from NutraSweet, Switzerland (batch no. C000220), Sodium carbonate was purchased from Aldrich. Germany (batch no. A008729PI), Sodium hydrogen carbonate was purchased from Merck, Germany (batch no. K28409723047), Sodium triphosphate was purchased from Sigma, USA (supplied from Swedish Match Sweden).

(29) 150 mg of the compositions E-J, respectively, were filled into snuff bags made of a snuff bag material obtained from Swedish Match, Sweden (batch no. W-NR00217, RL-NR6). The snuff bag size used is similar to the present marketed dry snuff bags, i.e. as Catch dry.

Example 2

(30) In vitro Release from Snuff Bag Compositions E, F, G, H, I and J

(31) Measurement of in vitro release rates of nicotine from snuff bags were performed using an in vitro dissolution test developed at Swedish Match, Stockholm, and utilizing a plastic flow-chamber in a tube with buffer solution combined with UV detection on a spectrophotometer at 260 nm. The details are mentioned above under the heading In vitro dissolution test.

(32) The in vitro release of nicotine from compositions E-J in percentage of the total content of nicotine are stated in the table below:

(33) TABLE-US-00004 COMPOSITION Compo- Compo- Compo- Compo- Compo- Compo- sition E sition F sition G sition H sition I sition J Nicotine 6.00 6.00 6.00 4.00 4.00 6.00 content (mg) 2.6 2.6 2.6-2.7 1.8 1.6-1.7 3.0 In vitro release, 30 min (mg) Percentage 43% 43% 43-45% 45% 40-42% 50% of released nicotine

(34) Furthermore, comparison studies of the in vitro release profiles of nicotine from snuff bags containing snuff compositions according to the present invention and already marketed snuff bags were performed. In FIG. 4 the in vitro release profiles of nicotine from compositions F and H were compared with the in vitro release profiles of nicotine from the present marketed dry snuff bags Catch dry and general white using the first of the above-mentioned in vitro release methods. FIG. 4 illustrates the improved in vitro release of nicotine from snuff compositions according to the present invention compared to both Catch dry and general white: Snuff composition F which contains 6 mg nicotine releases significantly more nicotine than the already marketed products Catch dry and general white. As the marketed products are natural products information of the exact content of nicotine is not available, but it is disclosed that the weight is 1 gram or less, the nicotine content is 5-11 mg, the pH is 7.3-8.5 and the buffer content is 1.5-3.5%.

(35) In FIG. 5 the in vitro release rates of nicotine from snuff compositions E, F and G containing 6 mg of nicotine and snuff compositions H and I containing 4 mg of nicotine, were compared to the in vitro release rates of nicotine from General compositions 1, 2 and 3. Again, the snuff compositions according to the present invention exhibit a better release relative to the total content of nicotine in the composition/product.

Example 3

(36) In Vivo Uptake of Nicotine from Snuff Bag Containing Composition

(37) A comparison study of the in vivo uptake of nicotine from the snuff product General, 4 mg Nicorette chewing gum and a snuff bag comprising composition I was performed. Composition J contained 0.8% sodium hydrogen carbonate and 0.8% sodium carbonate. Blood samples were taken at 0, 5, 10, 15, 20, 30 and 40 minutes after application and the plasma concentrations of nicotine were determined by ABS laboratories, London, England. After addition of sodium hydroxide, the plasma samples were extracted with dichloroethane and nicotine was quantitatively determined by gas chromatography using a nitrogen/phosphorous detector. 5-methyl cotinine was used to internally standardize the procedure. The limit of quantification is 0.5 ng/ml.

(38) The results are shown in FIG. 6. For comparison reasons the in vivo uptake of nicotine from the snuff product General was normalized to a nicotine content of 6 mg. FIG. 6 shows that over a time period of 30 minutes, the snuff bag containing composition J provides a plasma level of nicotine exceeding those of both General and Nicorette 4 mg nicotine chewing gum.

(39) Furthermore, a pilot pharmacokinetic study (n=4) in which the in vivo uptake of nicotine from snuff compositions G. J and I were compared to the in vivo uptake from Nicorette 4 mg chewing gum. The result shown in FIG. 7 illustrates that the in vivo uptake of nicotine from each of these snuff compositions is significantly better than from Nicorette 4 mg chewing gum.

Example 4

(40) Residual Amounts of Nicotine in Snuff Bags Comprising Snuff Compositions G, I and JIn Vitro Vs. In Vivo

(41) Snuff bags comprising either of compositions G, I or J were subjected to either the above-mentioned in vitro dissolution test employing USP basket apparatus or the above-mentioned pilot pharmacokinetic assay in 30 minutes. Subsequently, the residual nicotine content in the snuff bags was investigated using a dissolution bath combined with a UV-detection on a spectrophotometer at 260 nm. The dissolution was determined according to the dissolution method for tablets USP (basket) using 500 ml water as dissolution medium and a temperature of 37 C.

(42) The results are shown in the following table:

(43) TABLE-US-00005 Composition Composition Composition Snuff composition I G J Measured nicotine assay (mg) 3.8 6.3 6.3 Mean in vitro residual amount 1.9 3.6 3.3 nicotine after 30 minutes (n = 2) (mg) Mean in vitro residual amount 50 57 52 nicotine after 30 minutes (n = 2) (%) Mean in vivo residual amount 1.98 3.06 2.84 nicotine after 30 minnies (n = 4) (mg) Mean in vivo residual amount 52 49 45 nicotine after 30 minutes (n = 4) (%) Diversion in vitro vs in vivo 2 +8 +7 (% vs %)

(44) It follows from the figures in the above table, that the residual amount of nicotine in the snuff bags after 30 minutes of in vitro dissolution test is between 50% and 57% of the initial content of nicotine, i.e. between 43% and 50% of the nicotine has been released in the in vitro dissolution test. It further follows that the residual amount of nicotine in the snuff bags after 30 minutes of the in vivo pharmacokinetic study, is between 45% and 50% of the initial content of nicotine, i.e. between 45% and 50% of the nicotine has been absorbed in the bloodstream.

Example 5

(45) Comparison of Nicorette 4 mg Gum with MCC-Nicotine Containing Snuff Composition with 5 Mg Nicotine

(46) Single dose pharmacokinetics was studied in four subjects in comparison to Nicorette 4 mg gum (FIG. 8), FIG. 8 shows the results from a single dose pharmacokinetic study in four subject comparing Nicorette 4 mg chewing gum with a snuff composition containing MCC-nicotine corresponding to 5 mg nicotine after oral application.

(47) The bioavailability of nicotine from the nicotine snuff composition appears higher that that seen for the Nicorette composition even if the different in dosage is taken into account.

REFERENCES

(48) All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

(49) Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, and composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.