Succinate salt of cytisine and use thereof

Abstract

To provide a novel salt of cytisine, and to provide pharmaceutical compositions comprising the salt, in particular, to provide a salt of cytisine which displays improved excipient compatibility, permitting the preparation of stable pharmaceutical compositions.SOLUTION: Provided is a succinate salt of cytisine, the salt being in the form of a solvate or hydrate. Further provided is a pharmaceutical composition comprising the salt and a pharmaceutically acceptable excipient, the pharmaceutical composition being in the form of a tablet or a capsule, the pharmaceutical composition being provided as a unit dosage form, the unit dosage form comprising 1 mg to 3 mg of cytisine hydrogen succinate, and the pharmaceutical composition being for use in the treatment of nicotine addiction.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to novel salts of cytisine. The present invention also relates to pharmaceuticals containing novel cytisine salts. Concerning the composition. [Background technology]

[0002] Cytisine is a peptide known to be a potent nicotinic acetylcholine receptor agonist. It is a lysine-like alkaloid. Pharmacologically, cytisine shows a high degree of similarity to nicotine. Numerous studies have shown that cytisine is useful in treating nicotine addiction. .

[0003] Smoking cessation products containing cytisine have been commercially available for several years under the trade name Tabex®. The Tabex® product is an oral dose containing 1.5 mg of cytisine free base. It is available commercially in tablet form. The product has proven effective and has been a commercial success. However, the approved shelf life of the product is two years.

[0004] As will be appreciated by those skilled in the art, a two-year shelf life is generally accepted for pharmaceutical products; This is a major obstacle for manufacturers and suppliers in quickly packaging, transporting and delivering products to users. This puts pressure on the supply chain and increases the risk of inventory wastage if it exceeds its shelf life. In addition, if the product is intended for use in hot / humid climates (e.g. ICH climactic zones), e) Protect the product and maintain its shelf life when shipped to regions III and IV) Additional packaging may be required for

[0005] The prior art has proposed a number of formulation approaches for cytisine-containing products. For example, European Patent No. 1586320 discloses a solid dosage formulation containing cytisine free base. The document states that the formulations disclosed provide improved stability. There is no suggestion that this could be achieved by the use of a salt of cytisine. No salts of cytisine are disclosed.

[0006] WO 2014 / 076680 is also said to improve the stability of cytisine. As in EP 1586320, the present application discloses a cytisine-containing formulation. There is no suggestion or mention of the use of salts of cytisine to improve stability. In WO 2014 / 076680, the incompatibility between the active ingredient cytisine and lactose was Specifically, lactose is not completely chemically inert and Due to the presence of carboxyl groups in the lactose molecule which can cause the Illard reaction, It is stated that it may destabilize tablets containing cytisine. Summary of the Invention

[0007] Thus, the art has developed a method for preparing a glycerol-based ... A suitable form of cytisine is needed.

[0008] The present inventors have surprisingly and unexpectedly demonstrated improved excipient compatibility and have demonstrated that In a further embodiment, novel salts of cytisine that can be formulated with lactose have been identified.

[0009] Thus, according to a first aspect of the present invention there is provided a succinate salt of cytisine. In certain embodiments, the salts may be present in the form of solvates or hydrates. , preferably cytisine hydrogen succinate.

[0010] As mentioned above, the improved compatibility of the salts allows for the preparation of stable pharmaceutical compositions. Thus, according to a second aspect of the present invention, there is provided a method for the preparation of a cytisine succinate salt and a pharma- ceutically acceptable A pharmaceutical composition is provided that includes a carrier.

[0011] In one embodiment, the pharma- ceutical acceptable carrier is lactose. It may be lactose monohydrate or anhydrous lactose.

[0012] The compositions disclosed herein are suitable for administration by any route known in the art. Pharmaceutical formulations encompassed by this aspect of the invention include those for oral, nasal or topical administration. In one embodiment, the composition is in the form of a tablet or capsule. It may be formulated in solid form.

[0013] With regard to excipients that may be used in the compositions of the present invention, these include fillers, disintegrants, preservatives, Use of additives such as stearate, lubricants, and / or wetting agents may also be included. Examples of fillers that can be used include lactose (anhydrous or monohydrate), cellulose, starch. (e.g., corn and / or wheat starch), calcium phosphate, mannitol These include fluorouracil and others known in the art.

[0014] Preservatives prevent bacterial or fungal contamination of the formulation and are free of parabens, chlorobutanol, phenols, The composition may include various antibacterial and antifungal agents such as ethanol or sorbic acid.

[0015] Pharmaceutical compositions can be prepared according to any method known in the art, for example, by using Kollidon or Shear. Coating with lac, gum arabic, talc, titanium dioxide or sugar This can be done.

[0016] The pharmaceutical compositions of the present invention may further comprise sweetening, flavoring or coloring agents.

[0017] In embodiments of the invention in which pharmaceutical compositions are provided in the form of capsules, these may optionally For example, such capsules may be prepared by dissolving the salt in lactose or other suitable liquid. or sorbitol and filled into gelatin capsules. can be prepared.

[0018] In an embodiment of the invention, the pharmaceutical composition is provided in a unit dosage form (e.g., tablet, capsule) The amount of cytisine succinate salt in the composition is about 0.5 mg or about 1.0 mg. In some embodiments, the range may be from about 1.0 mg to about 2.0 mg, 3.0 mg, 5.0 mg, or about 10 mg. In the form of the pharmaceutical composition of the present invention, the pharmaceutical composition is stored at 25° C. and 60%±5% relative humidity. In some cases, the shelf life may be greater than two years. Although overlapping with other descriptions, the present invention is described below. [Invention 1] Cytisine succinate. [Invention 2] 2. The salt according to claim 1, wherein the salt is cytisine hydrogen succinate. [Invention 3] A solvate or hydrate of the salt according to invention 1 or 2. [Invention 4] A pharmaceutical composition comprising the salt according to any one of claims 1 to 3 and a pharma- ceutical acceptable excipient. Composition. [Invention 5] 5. The pharmaceutical composition according to claim 4, which is in the form of a tablet or capsule. [Invention 6] The pharma- ceutical acceptable excipient may be lactose, corn starch, and / or wheat starch. The pharmaceutical composition according to invention 4 or 5, which is starch. [Invention 7] Provided as a unit dosage form containing 1 to 3 mg of the salt according to any one of claims 1 to 3, 7. The pharmaceutical composition according to any one of claims 4 to 6. [Invention 8] A pharmaceutical composition according to any one of claims 4 to 7 for use in the treatment of nicotine addiction. thing. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows HPLC chromatograms of cytisine at (a) 310 nm and (b) 203 nm. [Diagram 2] FIG. 1 shows HPLC chromatograms of succinic acid at (a) 310 nm and (b) 203 nm. [Diagram 3] FIG. 1 shows HPLC chromatograms of cytisine succinate at (a) 310 nm and (b) 203 nm. [Figure 4] FIG. 1 shows (a) ESI+ and (b) ESI− HRMS spectra of cytisine succinate. [Diagram 5] FIG. 1 shows (a) ESI+ and (b) ESI− MS-MS spectra of cytisine succinate. [Figure 6] FIG. 1 shows (a) FTIR and (b) FTIR(ATR) IR spectra of cytisine succinate. [Figure 7] FIG. 1 shows peak purity determination using a DAD detector for (a) succinic acid and (b) cytisine for cytisine hydrogen succinate.

[0020] Various embodiments of the present invention will be further described with reference to the following examples.

[0021] Example 1: Preparation of Cytisine Succinate Salt An aqueous mixture of cytisine and succinic acid was prepared. The chromatograms are shown in Figures 1 and 2. Acetone was added to the mixture, and succinic acid was obtained in about 70% yield. The cytisine salt was isolated.

[0022] The starting materials (cytisine and succinic acid) and the resulting salts were analyzed using several analytical methods. The salts were characterized by the following methods (see Figures 1-7). The results are shown in Table 1 below. The purity was determined using HPLC and found to be greater than 99.9% (Figure 3). As can be seen, the salts of the present invention can be readily produced in very high purity using conventional salting out methods. It is possible.

[0023] The resulting salts were analyzed by high-resolution mass spectrometry (Figure 4), tandem mass spectrometry (Figure 5), and I R spectroscopy (Figure 6) and UV / VIS analysis (Figure 7) were performed.

[0024] [Table 1]

[0025] Example 2: Stability of cytisine succinate salt A sample of the cytisine succinate salt obtained from Example 1 was examined for its stability and the relative stability of the excipients used. These formulations were formulated in standard formulations to check the compatibility with the API. The analysis showed that the succinate-containing formulation was significantly more stable than the cytisine free base-containing formulation. This indicates that.

[0026] Example 3 - Salt Screening Stock solutions of acid salt formers are prepared in the carrier solvent with the molar concentrations detailed in the table below. Made by: [Table 2]

[0027] Stock solutions of cytisine API (non-synthetic) were also prepared in CH3CN and 2-Me-THF. 2.4 g of cytisine was dissolved in 24 ml of CH3CN heated to 40°C. .4 g of cytisine was dissolved in 60 ml of 2-Me-THF heated to a temperature of 60°C.

[0028] Add 2 ml of cytisine / CH3CN stock to a 10 ml tube heated to 40°C. solution or 5 ml of cytisine 2-Me-THF stock solution. The solution was added to the heated tube in equimolar amounts. The solution was kept at 40°C for 1 hour and then cooled to room temperature. Allow to cool to ambient temperature (approximately 18°C) for 18 hours. If solid formation does not occur spontaneously, i) immerse under nitrogen ii) antisolvent injection / trituration; iii) under nitrogen The procedure was repeated by blowing in 100 ml of TBME and triturating with 3 ml of acetone. The work was carried out.

[0029] The resulting solid was then filtered using a PTFE frit column. The product was then dried at 50° C. for 48 hours. The properties of the product were then analyzed. The following table shows the properties of the product. A summary of the screening results and properties of the products obtained; [Table 3]

[0030] As shown in the figure, suitable salts can be prepared by adding the common acid salt formers acetic acid, ascorbic acid or ammonium phosphate. However, the succinate salt was readily formed and was It showed advantageous properties.

[0031] Example 4 - Lactose incompatibility test Cytisine, 0.9541 g, was dissolved in 1 ml of water to give a yellow solution. Succinic acid, 0.59 19 g, 1 equivalent, was added as a solid to the cytisine solution and allowed to slowly dissolve with stirring. Acetone (10 ml) was added, and the bottom part was a solution of cytisine / succinic acid / water, and the top part was acetone. A portion of the cytisine / succinic acid / water solution was dissolved in acetone (10 ml). Trituration with 100 ml of ethyl acetate converted the viscous mixture into a precipitated white solid. Add the solution to the rest of the cytisine / succinic acid / water solution / acetone mixture and add 10 ml of acetone. This resulted in a viscous cytisine / succinic acid / water mixture that was then rinsed with water and stirred continuously. The mixture was converted to a white suspension which precipitated when stopped. The solid was isolated by filtration and heated at 50° C. The solid was dried in vacuum for about 16 hours. 1 H NMR analysis revealed that succinic acid It was confirmed to be Shin.

[0032] Recovery: 1.5463 g, 80% based on a 1:1 salt stoichiometry of cytisine to succinic acid. .76% The stability of binary mixtures of cytisine / lactose and cytisine succinate / lactose was 9 days at 40°C and 75% relative humidity (RH) in vials with loose caps Evaluated.

[0033] The sample mixtures and storage conditions used are detailed in Tables 2 and 3.

[0034] [Table 4]

[0035] [Table 5]

[0036] At the start of the stability study, the chemical purity of the cytisine / lactose mixture was 99.83 area %. and the cytisine succinate / lactose mixture was 99.68 area %.

[0037] At the end of the stability period, the following results were observed:

[0038] [Table 6]

[0039] As can be seen from the data in Table 4, when present in the succinate form, cytisine It decomposes at a substantially slower rate than when it is present in its base form. The compound effectively improves the stability of cytisine and facilitates its formulation in compositions containing lactose. Make it easier.

Claims

1. A unit dosage containing a succinate salt of cytisine, the salt being cytisine hydrogen succinate. wherein the unit dosage is an oral, nasal, or topical unit dosage.

2. 2. The dosage unit of claim 1, wherein the succinate salt of cytisine is a solvate or hydrate.

3. The succinate salt of cytisine is a pharmaceutical composition comprising the succinate salt and a pharma- ceutical acceptable excipient.

3. The dosage form according to claim 1 or 2, which is formulated as a pharmaceutical composition.

4. 10. The dosage form of claim 1, in the form of a tablet or capsule.

5. The pharma- ceutical acceptable excipients are selected from lactose, corn starch, and wheat starch. The dosage unit according to claim 3, selected from the group consisting of:

6. The composition according to any one of claims 1 to 5, comprising 1 to 3 mg of the succinate salt of cytisine. Unit dose.

7. A dosage unit according to any one of claims 1 to 6 for use in the treatment of nicotine addiction. 。

8. The dosage unit according to any one of claims 1 to 7, which is an oral dosage unit.

9. The dosage unit according to any one of claims 1 to 7, which is a nasal dosage unit.

10. The dosage form according to any one of claims 1 to 7, which is a topical dosage form.

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