HK1194741A - Pharmaceutical composition comprising amide derivative inhibiting the growth of cancer cells and non-metallic salt lubricant - Google Patents

Description

Pharmaceutical composition comprising an amide derivative that inhibits cancer cell growth and a non-metallic salt lubricant

Technical Field

The present invention relates to pharmaceutical compositions comprising an amide derivative or a pharmaceutically acceptable salt thereof that inhibits the growth of cancer cells and a non-metallic salt lubricant.

Background

Epidermal Growth Factor Receptor (EGFR) is known to have 4 receptor subtypes, namely EGFR/ErbB1, Her-2/ErbB2, Her-3/ErbB3, and Her-4/ErbB 4. They are abnormally overexpressed in most solid tumor cells. Moreover, activation of the receptor by the ligand leads to activation of cell signaling pathways, which lead to growth, differentiation, angiogenesis, metastasis, and resistance of tumor cells (a. wells, int.j. biochem. cell biol., 1999, 31, 637-643). Thus, blocking epidermal growth factor receptor-mediated tumor cell signaling pathways would be expected to produce an anti-tumor effect. Accordingly, many research efforts for developing anticancer drugs targeting epidermal growth factor receptors have been made.

Such anti-cancer drugs targeting the epidermal growth factor receptor fall into two categories: monoclonal antibodies targeting the extracellular domain and small molecule drugs targeting intracellular tyrosine kinases. The monoclonal antibody has the advantages of good drug effect and small side effect due to the selective combination of the monoclonal antibody on the epidermal growth factor receptor. However, monoclonal antibodies have the disadvantage of being very expensive and have to be administered by injection. At the same time, small molecule drugs targeting tyramine kinase are relatively inexpensive and can be administered orally, and also have good efficacy by reacting selectively or simultaneously with the receptor subtypes (e.g., EGFR, Her-2, Her-3, and Her-4).

Examples of such small molecule drugs include selective inhibitors of EGFR, e.g.(Gefitinib, AstraZenaca) with(Erlotinib), Roche); and dual inhibitors that block both EGFR and Her-2, e.g.(Lapatinib), GlaxoSmithKline). These drugs are currently used to treat lung cancer and advanced Her-2 positive breast cancer, respectively. Therefore, clinical trials are also being conducted to improve efficacy against other solid tumors.

A recent study has reported that a second mutation (i.e., a substitution of threonine to methionine at amino acid position 790 within the Adenosine Triphosphate (ATP) binding site of the EGFR tyrosine kinase domain) can reduce the binding capacity of the drug, which results in a significant reduction in the response rate of the drug (c.h. gow, et al, PLoS med., 2005, 2(9), e 269). Therefore, there is a need to develop drugs with enhanced inhibitory activity against EGFR-resistant cancer cells.

Korean patent laid-open No.2008-0107294 discloses a compound of formula (I) which selectively and effectively inhibits the growth of cancer cells and the development of drug resistance induced by EGFR and mutants thereof without side effects. However, it has been found that pharmaceutical formulations comprising a compound of formula (I) as active ingredient and pharmaceutically acceptable additives thereof will facilitate the formation of compounds of formula (II) (hereinafter referred to as related compounds IV) under certain storage conditions, thereby reducing the amount of compounds of formula (I).

The purity of the active ingredient is an important factor for the preparation of safe and effective pharmaceutical compositions, since certain impurities contained in the drug may cause side effects during the treatment. Some impurities may be removed during the preparation of the drug. However, due to variations in various conditions such as temperature, humidity, and light, some substances resulting from degradation of the drug may remain as impurities.

The present inventors have endeavored to investigate the factors by which pharmaceutical formulations comprising a compound of formula (I) can promote the formation of the relevant compound IV during storage, and have found that pharmaceutically acceptable additives, in particular metal salts contained in lubricants, lead to an accelerated formation of the relevant compound IV. Accordingly, the present inventors have developed a pharmaceutical composition with enhanced stability by employing a non-metallic salt lubricant (which does not contain a metallic salt component).

Summary of The Invention

An object of the present invention is to provide a pharmaceutical composition having improved stability comprising an amide derivative or a pharmaceutically acceptable salt thereof effective in inhibiting the growth of cancer cells.

According to one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a non-metallic salt lubricant:

brief Description of Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention when taken in conjunction with the accompanying drawings which respectively show:

FIG. 1 is a schematic diagram: stability test results showing the amount of the related compound IV generated after heating the pharmaceutical compositions of examples 1 to 8 and comparative example 1 at 60 ℃;

FIG. 2 is a schematic diagram: stability test results showing the amount of the related compound IV generated after heating the pharmaceutical compositions of comparative examples 1 to 4 and example 1 at 60 ℃;

FIG. 3 is a schematic diagram: accelerated stability test results showing the amount of related compound IV produced after exposing the pharmaceutical compositions of examples 1 and 2 and comparative examples 1 and 3 to accelerated conditions (40 ℃ and 75% RH); and

FIG. 4 is a schematic view of: accelerated stability test results in HDPE bottles showing the amount of related compound IV produced after exposing the pharmaceutical compositions of examples 1 and 2 and comparative examples 1 and 3 to accelerated conditions (40 ℃ and 75% RH).

Detailed Description

The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a non-metallic salt lubricant:

each component of the pharmaceutical composition of the present invention is described in detail below.

(a) Pharmaceutical active ingredient

The pharmaceutical composition according to the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient.

The compound of formula (I) (hereinafter referred to as "HM 781-36B") disclosed in Korean patent publication No.2008-0107294 selectively and effectively inhibits the growth of cancer cells and the development of drug resistance induced by EGRF and mutants thereof without causing adverse side effects.

Pharmaceutically acceptable salts of compounds of formula (I) include, but are not limited to: acid addition salts of inorganic or organic acids. Examples of the inorganic acid addition salt may include hydrochloride, sulfate, disulfonate, nitrate, phosphate, perchlorate, or bromate; examples of organic acid addition salts may include formate, acetate, propionate, oxalate, succinate, benzoate, citrate, maleate, malonate, malate, tartrate, gluconate, lactate, gentisate, fumarate, lactobionate, salicylate, phthalate, embonic acid (aspirin), aspartate, glutamate, camphorsulfonic acid (camsylacid), benzenesulfonate or acetylsalicylic acid (aspirin) salts. Pharmaceutically acceptable salts can also include metal salts derived from alkali metals (e.g., calcium, sodium, magnesium, strontium, potassium, and the like).

In the present invention, the compound of formula (I) is used in an amount ranging from 0.1 to 5.0%, preferably from 0.5 to 10%, by weight of the total composition. The amount of compound in the composition may range from 0.1mg to 100mg, preferably from 0.5 to 50mg, per 1 dosage unit of the composition.

(b) Non-metallic salt lubricant

Lubricants are ingredients added to improve the compression process of granules, and lubricants are considered as important excipients, which play an important role in the preparation of solid compressed compositions. Advantages of using lubricants include improved flow of powder or granular material, which allows them to be more easily packed in a die (die); reduced friction of the powder or granular material and reduced friction between the powder or granular material and the punch (punch) or die; and enhanced compressibility and dischargeability of the tablet. The lubricants may be classified as shown in table 1.

< Table 1>

The pharmaceutical composition of the present invention comprising the compound of formula (I) is characterized in that the formation of the related compound IV is prevented by using a non-metallic salt lubricant, and if the composition contains a metallic salt, the related compound IV is formed from the metallic salt.

The term "non-metallic salt lubricant" according to the present invention refers to a lubricant free of metallic substances (e.g. such metallic salts as calcium stearate, magnesium stearate, sodium stearyl fumarate, zinc stearate, etc.). Examples of the non-metallic salt lubricant according to the present invention may include fatty acid esters, fatty acids, fatty alcohols, oils, fumaric acid, polyethylene glycol (PEG), polytetrafluoroethylene, starch, talc, and the like. Enhanced storage stability of the pharmaceutical compositions of the present invention may be achieved by the use of such non-metallic salt lubricants.

Specifically, examples of non-metallic salt lubricants useful in the present invention may include, but are not limited to: fatty acid esters (e.g., glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl trimyristate, glyceryl tristearate, sucrose fatty acid esters, etc.); fatty acids and fatty alcohols (e.g., palmitic acid, palmitoyl alcohol, stearic acid, stearyl alcohol, etc.); oils (e.g., hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, etc.); fumaric acid; polyethylene glycol (e.g., PEG4000 or PEG 6000); polytetrafluoroethylene; starch; and talc. The non-metallic salt lubricant may be used alone or as a mixture thereof.

Preferably, exemplary non-metallic salt lubricants according to the present invention may include sucrose fatty acid esters, hydrogenated vegetable oil, stearic acid, glyceryl behenate, glyceryl palmitostearate, talc, starch, and PEG6000, more preferably sucrose fatty acid esters and hydrogenated vegetable oil.

In the present invention, the non-metal salt lubricant may be used in an amount ranging from 0.1 to 100 parts by weight, preferably from 0.1 to 50 parts by weight, more preferably from 0.25 to 10 parts by weight, based on 1 part by weight of the compound of formula (I).

If the non-metallic salt lubricant is used in an amount of less than 0.1 parts by weight, the formed tablet cannot be easily released from the mold during the formation of the tablet, or may stick to the mold. On the other hand, if the amount is more than 100 parts by weight, problems such as capping or delamination (deletion) of the tablet may occur. Furthermore, since lubricants are generally hydrophobic, if used in large amounts, they can cause undesirable problems such as delayed disintegration and low dissolution.

(c) Pharmaceutically acceptable additives

The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable additives and may be formulated into various administration forms, preferably oral administration forms. Representative examples of formulations for oral administration may include powders, tablets, pills, capsules, liquids, suspensions, emulsions, syrups, and granules, preferably tablets and capsules, but are not limited thereto.

In the present invention, the pharmaceutically acceptable additives may include diluents, binders, disintegrants and the like.

Examples of the diluent may include microcrystalline cellulose, lactose, mannitol, calcium phosphate, and the like; examples of the binder may include povidone, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), sodium carboxymethylcellulose, etc.; examples of disintegrants may include crospovidone, croscarmellose sodium, sodium starch glycolate, and the like.

The diluent may be used in an amount ranging from 20% to 95%, the binder may be used in an amount ranging from 1% to 10%, and the disintegrant may be used in an amount ranging from 1% to 30%, based on the total weight of the composition.

The pharmaceutical composition of the present invention may be coated with a coating base to prevent the composition from directly contacting the hands or skin of a user.

Coating substrates useful in the present invention may include rapid-release coating substrates (rapid-release coating substrates), enteric-coating substrates (enteric coating substrates), or sustained-release coating substrates (sustained release coating substrates). The fast release coating matrix may be selected from: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol-polyethylene glycol graft polymer (Kollocoat)BASF), and mixtures thereof. The enteric coating matrix may be selected from: (meth) acrylate copolymer (A)EVONIK), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and mixtures thereof. The sustained release coating matrix may be selected from: cellulose acetate, ethyl cellulose, polyvinyl acetate, and mixtures thereof.

The amount of the coating base that can be coated on the surface of the composition ranges from 1 to 50 parts by weight, preferably from 1 to 30 parts by weight, based on 100 parts by weight of the uncoated core.

The present invention also provides a process for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a non-metallic salt lubricant.

The formulation of the pharmaceutical composition comprising the above ingredients may be prepared by a process comprising the steps of:

(1) mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable additives such as diluents and binders, and granulating the mixture to obtain granules;

(2) mixing the granules prepared in step (1) with pharmaceutically acceptable additives such as a diluent and a disintegrant, and adding a non-metallic salt lubricant thereto to obtain mixed granules; and

(3) subjecting the mixed granules prepared in step (2) to a formulation step.

In one embodiment of the present invention, the pharmaceutical composition of the present invention may be prepared by the following steps: compound (I) and mannitol were mixed in a povidone solution in purified water, the mixture prepared was subjected to wet granulation, and the resulting granules were then dried. The prepared granules may be mixed with mannitol and crospovidone, a non-metallic salt lubricant is added thereto, and then the mixed granules are tableted by a tableting machine.

The various steps associated with the formulation of the pharmaceutical compositions of the present invention may be carried out according to conventional techniques known in the art. Furthermore, the method of the present invention may further comprise the steps of: a step of coating the preparation prepared in step (3) with the above-mentioned coating base for convenience of storage and ease of use.

The pharmaceutical composition of the present invention can effectively inhibit the growth of cancer cells by comprising the compound of formula (I) which selectively and effectively inhibits the growth of cancer cells and the development of drug resistance induced by EGFR and mutants thereof. Furthermore, by including a non-metallic salt lubricant, the pharmaceutical composition of the present invention can inhibit the formation of impurities (i.e., related compound IV) to less than 0.5% by weight under extreme conditions (e.g., 4 weeks in a gas-tight HDPE container at 60 ℃) and accelerated conditions (e.g., 6 months in a gas-tight HDPE container at 40 ℃/75% RH). Thus, the pharmaceutical compositions of the present invention may enhance potency and may improve the stability of the compounds of formula (I).

Accordingly, the present invention provides a method for stabilizing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising adding a non-metallic salt lubricant to the pharmaceutical composition.

The following examples are intended to further illustrate the invention without limiting its scope.

Examples

Examples 1 to 8: preparation of pharmaceutical compositions comprising non-metallic salt lubricants

By using a compound of formula (I) (hereinafter referred to as "HM 781-36B", Dongwoo Syntech co., ltd., Korea) according to the composition and amount (unit: mg) described in table 2; mannitol (Roquette);(BASF)；(BASF); and sucrose fatty acid ester (Daiichi Kogyo Seiyaku, Japan) as a non-metallic salt lubricant, hydrogenated vegetable oil: (JRS Pharma), or stearic acid (Emery Oleochemicals) to prepare the pharmaceutical compositions of examples 1 to 3.

Specifically, HM781-36B and mannitol were mixed and the mixture was wet granulated by conventional methods using povidone binder solution dissolved in purified water. The wet granules thus obtained were dried, mixed with mannitol and crospovidone, and then added with a lubricant that had previously been sieved through a 30 mesh sieve to prepare a final mixture. The final mixture thus prepared is formed into tablets having a hardness of about 5 to 10kp by a tablet press (Sejong, Korea) according to a conventional method.

< Table 2>

According to the compositions and amounts (unit: mg) described in table 3, the compound of formula (I) (HM781-36B, dongwooo Syntech co., ltd., Korea) was used by the same method as described above; mannitol (Roquette);(BASF)；(BASF); and glyceryl behenate (Compritol 888) as a non-metal salt lubricantGattefosse), glyceryl palmitostearate (Compritol)Gatefosse), Talc (Nippon Talc Corp., Japan), starch (Roquette), or PEG6000(Sanyo Chemical, Japan) the pharmaceutical compositions of examples 4 to 8 were prepared.

< Table 3>

The compound of formula (I) (HM781-36B, Dongwoo Syntech co., ltd., Korea) was used by the same method as above according to the composition and amount (unit: mg) described in table 4; mannitol (Roquette);(BASF)；(BASF); and glyceryl monostearate (Capmul GMS-50), palmitoyl alcohol (randz international Company ltd., China), stearyl alcohol (Lubrizol advanced materials, u.s.), hydrogenated castor oil (BASF), mineral oil (Alfa Aesar, u.s.), fumaric acid (Merck), or silicon dioxide (Grace Davison, u.s.) as a non-metal salt lubricant.

< Table 4>

Comparative examples 1 to 4: preparation of pharmaceutical compositions comprising metal salt lubricants

The methods of the above examples were repeated by using the compositions and amounts (unit: mg) described in table 5 to prepare the pharmaceutical compositions of comparative examples 1 to 4 containing the metal salt lubricant.

< Table 5>

Test examples: measuring the related compounds formed

To evaluate the storage stability of the pharmaceutical compositions prepared in examples 1 to 8 and comparative examples 1 to 4, each pharmaceutical composition was packaged in 1g of silica gel in an HDPE bottle and stored in a chamber (chamber) (60 ℃). After 2 and 4 weeks, respectively, the relevant compound IV (major degradation product of HM 781-36B) was extracted by 60% acetonitrile as a solvent and then subjected to HPLC analysis. The results of examples 1 to 8 are shown in table 6 and fig. 1, and the results of comparative examples 1 to 4 are shown in table 7 and fig. 2.

< Table 6>

Examples	1	2	3	4	5	6	7	8
									Initial	0.05	0.04	0.04	0.05	0.05	0.04	0.04	0.05
2 weeks at 60 deg.C	0.26	0.23	0.17	0.27	0.21	0.15	0.18	0.37
									4 weeks at 60 deg.C	0.34	0.35	0.31	0.38	0.36	0.26	0.29	0.45

< Table 7>

Comparative example	1	2	3	4
					Initial	0.04	0.04	0.04	0.04
2 weeks at 60 deg.C	1.52	0.98	1.60	1.09
					4 weeks at 60 deg.C	2.46	2.25	3.41	1.98

In order to observe the change in stability to temperature and humidity of the pharmaceutical compositions prepared according to examples 1 and 2 and comparative examples 1 and 3, the pharmaceutical compositions were exposed to 40 ℃ and 75% RH. After 1 and 2 weeks, respectively, the relevant compound IV (major degradation product of HM 780-36B) was extracted by 60% acetonitrile as a solvent and then subjected to HPLC analysis. The results are shown in table 8 and fig. 3.

< Table 8>

	Example 1	Example 2	Comparative example 1	Comparative example 3
					Initial	0.05	0.04	0.04	0.04
1 week 40 ℃/75% RH	0.12	0.10	0.73	0.32
					2 weeks 40 ℃/75% RH	0.16	0.15	1.18	0.51

To observe the change in stability to temperature and humidity under accelerated conditions for the pharmaceutical compositions prepared according to examples 1 and 2 and comparative examples 1 and 3, the compositions were exposed to 40 ℃ and 75% RH in sealed HDPE containers for 1, 3 and 6 months. The related compound IV of each composition was extracted by 60% acetonitrile as a solvent, and then subjected to HPLC analysis. The results are shown in table 9 and fig. 4.

< Table 9>

	Example 1	Example 2	Comparative example 1	Comparative example 3
					Initial	0.05	0.04	0.04	0.04
1 month ACLTD40 deg.C	0.15	0.14	0.31	0.28
					3 months of ACLTD40 deg.C	0.17	0.15	0.41	0.32
6 months of ACLTD40 deg.C	0.20	0.18	0.62	0.58

As shown in tables 6 to 9 and fig. 1 to 4, the formation of related compound IV was reduced by about 4 to 10-fold or more in the pharmaceutical composition comprising any of the non-metallic salt lubricants compared to the pharmaceutical composition comprising the metallic salt lubricant. Thus, the storage stability of a pharmaceutical composition comprising HM781-36B as an active ingredient may be enhanced by adding any non-metallic salt lubricant to the pharmaceutical composition.

The limits for unknown and known impurities are specified to be 0.2% and 0.5%, respectively, according to guidelines of the International conference on harmony of Technical Requirements for Registration of drugs for Human Use (ICH). The pharmaceutical compositions according to examples 1 and 2 of the present invention showed satisfactory results of less than 0.5% in the accelerated stability test as described in this ICH guidelines at 40 ℃. In contrast, the pharmaceutical compositions of comparative examples 1 and 3, which contain conventional metal salt lubricants, exceeded the predetermined limits of the ICH guidelines.

Although the invention has been described with reference to the above specific embodiments, it will be appreciated that numerous modifications and variations of the invention may be made by those skilled in the art which also fall within the scope of the invention as defined in the appended claims.

Claims (16)

1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a non-metallic salt lubricant:

2. the pharmaceutical composition of claim 1, wherein the non-metallic salt lubricant is selected from the group consisting of: fatty acid esters, fatty acids, fatty alcohols, oils, fumaric acid, polyethylene glycol (PEG), polytetrafluoroethylene, talc, and mixtures thereof.

3. The pharmaceutical composition of claim 2, wherein the non-metallic salt lubricant is selected from the group consisting of: glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl trimyristate, glyceryl tristearate, sucrose fatty acid esters, palmitic acid, palmitoyl alcohol, stearic acid, stearyl alcohol, hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, fumaric acid, PEG4000, PEG6000, polytetrafluoroethylene, starch, talc, and mixtures thereof.

4. The pharmaceutical composition of claim 3, wherein the non-metallic salt lubricant is a sucrose fatty acid ester or a hydrogenated vegetable oil.

5. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is present in an amount ranging from 0.1mg to 100mg per 1 dosage unit of the composition.

6. The pharmaceutical composition of claim 1, wherein the non-metallic salt lubricant is present in an amount ranging from 0.1 to 100 parts by weight based on 1 part by weight of the compound of formula (I).

7. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable additive selected from the group consisting of: diluents, binders, disintegrants, and mixtures thereof.

8. The pharmaceutical composition of claim 7, wherein the diluent is present in an amount ranging from 20% to 95% by weight of the total composition.

9. The pharmaceutical composition of claim 7, wherein the binder is present in an amount ranging from 1% to 10% by weight of the total composition.

10. The pharmaceutical composition of claim 7, wherein the disintegrant is present in an amount ranging from 1% to 30% by weight of the total composition.

11. The pharmaceutical composition of claim 1, which is coated with a coating matrix selected from the group consisting of: a rapid release coated substrate, an enteric coated substrate, and a sustained release coated substrate.

12. The pharmaceutical composition of claim 11, wherein the coating matrix is selected from the group consisting of: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymers, (meth) acrylic acid copolymers, hydroxypropyl methylcellulose phthalate, cellulose acetate, ethyl cellulose, polyvinyl acetate, and mixtures thereof.

13. The pharmaceutical composition of claim 1, comprising less than 0.5% by weight of a compound of formula (II) at 60 ℃ under extreme conditions of 4 weeks in a gas-tight HDPE container, or at accelerated conditions of 6 months at 40 ℃ and 75% RH in a gas-tight HDPE container:

14. a process for preparing a formulation of the pharmaceutical composition of claim 1, comprising the steps of:

(1) mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable additives and granulating the mixture to obtain granules;

(2) mixing the granules prepared in step (1) with pharmaceutically acceptable additives and adding a non-metallic salt lubricant thereto to obtain mixed granules; and

(3) subjecting the mixed granules prepared in step (2) to a preparation step,

15. the method of claim 14, further comprising the step of coating the formulation prepared in step (3) with a coating base selected from the group consisting of: a rapid release coated substrate, an enteric coated substrate, and a sustained release coated substrate.

16. A method for stabilizing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising adding to the pharmaceutical composition a non-metallic salt lubricant: