Pharmaceutical composition without antioxidant and containing pregelatinized starch

Abstract

The invention discloses a pharmaceutical composition which does not contain an antioxidant and contains pregelatinized starch. The invention provides a pharmaceutical composition. The pharmaceutical composition comprises a compound as shown in a formula (I), a filler, pregelatinized starch and a lubricant, the pharmaceutical composition does not contain an antioxidant. According to the pharmaceutical composition disclosed by the invention, the use of an antioxidant is avoided, and a preparation prepared from the pharmaceutical composition can keep relatively good stability. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an antioxidant-free pharmaceutical composition containing pregelatinized starch. Background Art

[0002] Compound (I) [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate (shown in Formula (I) below) is a gabapentin-like drug developed by Daiichi Sankyo Co., Ltd. of Japan, primarily used to treat diabetic and postherpetic neuralgia. This drug binds to and modulates the α2σ-1 subunit of the voltage-gated calcium channel. Compared with gabapentin and pregabalin, it has a more rapid time to peak plasma concentration, better bioavailability, and lower central nervous system-specific adverse drug reactions. A search revealed that the marketed tablet formulation contains antioxidants and is complex, making production control difficult.

[0003]

[0004] The compound (I) tablets of the original formulation patent (CN107405322B) are compositions containing antioxidants. Specifically protected are formulations prepared by combining compound (I) with one or two or more excipients, one or two or more disintegrants, and one or two or more antioxidants selected from the group consisting of sodium edetate, citric acid hydrate, butylated hydroxytoluene, propyl gallate, magnesium citrate (anhydrous), soy lecithin, tocopherol, tocopherol acetate, and β-cyclodextrin. Antioxidants can effectively control the growth of impurities during the stability period. However, antioxidants are added during the tablet compression process, which requires grinding, screening, mixing, tableting, and other unit operations, making the operation complex. Furthermore, antioxidants are prone to becoming sticky and affecting mixing uniformity, and their stabilization effect is uncontrollable. If the antioxidants are removed directly, the impurities in the formulation increase significantly, exceeding the limit. Even with the addition of various antioxidants, the impurities increased by more than 1.3% when examined under 40°C and 75% RH for one month, which may pose a safety risk after oral administration.

[0005] The original patent CN104334169A protects a solid composition containing milopalline besylate. Specifically, it protects compound (I) with the filler D-mannitol, the disintegrant carboxymethylcellulose calcium, and the lubricants magnesium stearate or sodium stearyl fumarate, prepared by a powder direct compression method. However, the tablets produced showed a decrease in the content of related substances to 1.65% after four weeks at 40°C and 75% RH, indicating poor stability. Summary of the Invention

[0006] The present invention has discovered that pregelatinized starch can improve the stability of Compound (I), overcoming the problems of existing pharmaceutical compositions of Compound (I) containing antioxidants, such as uncontrollable stability during tablet preparation or the excessive release of related substances after tablet storage. This provides a pharmaceutical composition containing pregelatinized starch without an antioxidant. The pharmaceutical composition of the present invention avoids the use of antioxidants, and the preparation prepared therefrom maintains good stability.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a pharmaceutical composition comprising a compound as represented by formula (I), a filler, pregelatinized starch and a lubricant;

[0009] The pharmaceutical composition does not include an antioxidant;

[0010]

[0011] In one embodiment, the compound of formula (I) accounts for 3-15% by weight of the pharmaceutical composition, preferably 6-12%, more preferably 8.5-10%, such as 8.75%, 8.95%, 8.96% or 9.16%.

[0012] In one embodiment, the filler is a conventional filler in the art, preferably directly compressible mannitol and / or microcrystalline cellulose. The directly compressible mannitol is preferably directly compressible mannitol M100.

[0013] In a certain embodiment, the filler accounts for 75-90% by weight of the pharmaceutical composition, preferably 80-90%, such as 80.79%, 83.16%, 85.51%, 85.52%, 85.53% or 87.6%.

[0014] In a certain embodiment, the directly compressible mannitol accounts for 35-90% by weight of the pharmaceutical composition, preferably 40-86%, such as 41.76%, 61.32%, 68.42%, 76.97% or 85.51%.

[0015] In a certain embodiment, the microcrystalline cellulose accounts for 5-50% by weight of the pharmaceutical composition, preferably 5-45%, such as 8.55%, 14.74%, 15.92%, 17.11%, 26.28% or 41.76%.

[0016] In a preferred embodiment, the directly compressible mannitol accounts for 60-80% of the pharmaceutical composition by weight.

[0017] In a preferred embodiment, the microcrystalline cellulose accounts for 5-30% by weight of the pharmaceutical composition.

[0018] In one embodiment, the lubricant is a conventional lubricant in the art, preferably selected from one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl monostearate, poloxamer, sodium benzoate, sodium lauryl sulfate and talc, such as magnesium stearate.

[0019] In a certain embodiment, the lubricant accounts for 0.1-5% by weight of the pharmaceutical composition, preferably 0.6-1%, more preferably 0.7-0.85%, such as 0.77%, 0.79% or 0.81%.

[0020] In a certain embodiment, the pregelatinized starch accounts for 1-15% by weight of the pharmaceutical composition, preferably 2-10%, for example 2.43%, 4.74%, 4.75%, 6.95%, 7.11% or 9.48%.

[0021] In a preferred embodiment, the pharmaceutical composition comprises the following components by weight:

[0022] 3-15% of the compound represented by formula (I), 75-90% of the filler, 1-15% of the pregelatinized starch and 0.1-5% of the lubricant;

[0023] Preferably, the pharmaceutical composition consists of the above components.

[0024] In a preferred embodiment, the pharmaceutical composition comprises the following components by weight:

[0025] The compound represented by formula (I), the filler, the pregelatinized starch and the lubricant;

[0026] The compound represented by formula (I) accounts for 8.75%, 8.95%, 8.96% or 9.16% of the pharmaceutical composition by weight;

[0027] The filler accounts for 80.79%, 83.16%, 85.51%, 85.52%, 85.53% or 87.6% of the pharmaceutical composition by weight;

[0028] The pregelatinized starch accounts for 2.43%, 4.74%, 4.75%, 6.95%, 7.11% or 9.48% of the pharmaceutical composition by weight;

[0029] The lubricant is 0.77%, 0.79% or 0.81% by weight of the pharmaceutical composition;

[0030] Preferably, the pharmaceutical composition consists of the above components.

[0031] In a preferred embodiment, the pharmaceutical composition comprises the following components by weight:

[0032] 3-15% of the compound represented by formula (I);

[0033] 75-90% of the filler, wherein the filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100;

[0034] 1-15% of the pregelatinized starch;

[0035] 0.1-5% of the lubricant, wherein the lubricant is magnesium stearate;

[0036] Preferably, the pharmaceutical composition consists of the above components.

[0037] In a preferred embodiment, the pharmaceutical composition comprises the following components by weight:

[0038] The compound represented by formula (I), the filler, the pregelatinized starch and the lubricant;

[0039] The compound represented by formula (I) accounts for 8.75%, 8.95%, 8.96% or 9.16% of the pharmaceutical composition by weight;

[0040] The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100;

[0041] The filler accounts for 80.79%, 83.16%, 85.51%, 85.52%, 85.53% or 87.6% of the pharmaceutical composition by weight;

[0042] The pregelatinized starch accounts for 2.43%, 4.74%, 4.75%, 6.95%, 7.11% or 9.48% of the pharmaceutical composition by weight;

[0043] The lubricant is magnesium stearate;

[0044] The lubricant is 0.77%, 0.79% or 0.81% by weight of the pharmaceutical composition;

[0045] Preferably, the pharmaceutical composition consists of the above components.

[0046] In a preferred embodiment, the directly compressible mannitol accounts for 60-80% by weight of the pharmaceutical composition, and the microcrystalline cellulose accounts for 5-30% by weight of the pharmaceutical composition.

[0047] In a preferred embodiment, the pharmaceutical composition comprises the following components by weight:

[0048] 3-15% of the compound represented by formula (I), 60-80% of the directly compressible mannitol, 5-30% of the microcrystalline cellulose, 1-15% of the pregelatinized starch and 0.1-5% of the lubricant;

[0049] Preferably, the pharmaceutical composition consists of the above components.

[0050] In a specific embodiment, the pharmaceutical composition comprises any combination of the following components by weight:

[0051] Combination 1: 8.95% of the compound of formula (I), 68.42% of directly compressible mannitol M100, 17.11% of microcrystalline cellulose, 4.74% of pregelatinized starch, and 0.79% of magnesium stearate;

[0052] Combination 2: 9.16% of the compound of formula (I), 61.32% of directly compressible mannitol M100, 26.28% of microcrystalline cellulose, 2.43% of pregelatinized starch, and 0.81% of magnesium stearate;

[0053] Combination 3: 8.95% of the compound of formula (I), 76.97% of directly compressible mannitol M100, 8.55% of microcrystalline cellulose, 4.74% of pregelatinized starch, and 0.79% of magnesium stearate;

[0054] Combination 4: 8.75% of the compound of formula (I), 41.76% of directly compressible mannitol M100, 41.76% of microcrystalline cellulose, 6.95% of pregelatinized starch, and 0.77% of magnesium stearate;

[0055] Combination 5: 8.96% of the compound of formula (I), 85.51% of directly compressible mannitol M100, 4.75% of pregelatinized starch, and 0.79% of magnesium stearate;

[0056] Combination 6: 8.95% of the compound of formula (I), 67.24% of directly compressible mannitol M100, 15.92% of microcrystalline cellulose, 7.11% of pregelatinized starch, and 0.79% of magnesium stearate;

[0057] Combination 7: 8.95% of the compound of formula (I), 66.05% of directly compressible mannitol M100, 14.74% of microcrystalline cellulose, 9.48% of pregelatinized starch, and 0.79% of magnesium stearate;

[0058] Preferably, the pharmaceutical composition consists of the above components.

[0059] In one embodiment, the pharmaceutical composition is a solid preparation, such as a tablet. The tablet can be a plain tablet or a coated tablet.

[0060] The present invention also provides a method for preparing the pharmaceutical composition as described above, which comprises the following steps: directly compressing the components of the pharmaceutical composition into tablets.

[0061] In one embodiment, the preparation method of the pharmaceutical composition comprises the following steps: screening, mixing, and tableting the compound represented by formula (I), the directly compressible mannitol, the microcrystalline cellulose, the pregelatinized starch, and the lubricant. The screening may be through a 40-mesh sieve.

[0062] The present invention also provides a use of the pharmaceutical composition described above in the preparation of a medicament for treating pain. The pain may be postherpetic neuralgia or diabetic neuropathy. The pain may be chronic pain, central neuropathic pain, or peripheral neuropathic pain. The central neuropathic pain may be central neuropathic pain after spinal cord injury (SCI).

[0063] As used herein, the term "antioxidant" refers to a class of substances that can help capture and neutralize free radicals, prevent or delay oxidation, and improve stability. Examples include calcium sodium edetate, citric acid, butylated hydroxytoluene, propyl gallate, magnesium citrate, soy lecithin, tocopherol, tocopherol acetate, β-cyclodextrin, ascorbic acid, sodium bisulfite, sodium sulfite, isoascorbic acid, cysteine ​​hydrochloride, sodium metabisulfite, butylated hydroxyanisole, or tartaric acid.

[0064] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0065] The reagents and raw materials used in the present invention are commercially available.

[0066] The present invention has the following positive advantages: It has been discovered that pregelatinized starch can improve the stability of Compound (I), providing a pharmaceutical composition that does not contain an antioxidant. The pharmaceutical composition of the present invention uses pregelatinized starch instead of an antioxidant, and the resulting formulation maintains good stability. After 30 days at 40°C and 75% relative humidity, the content of related substances is less than 0.5%. DETAILED DESCRIPTION

[0067] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0068] Example 1

[0069] Stability study of the formulations of pharmaceutical compositions without and with antioxidants and the preparations prepared therefrom.

[0070] 1.1 Combinations of drugs containing and without antioxidants

[0071] Table 1 Prescription composition of pharmaceutical compositions without and with antioxidants

[0072]

[0073] Preparation method:

[0074] (1) Compound (I), D-mannitol, microcrystalline cellulose, pregelatinized starch, carboxymethylcellulose calcium, magnesium stearate, and antioxidants (calcium sodium edetate, sodium metabisulfite, propyl gallate, L-tartaric acid, BHA, and cysteine ​​hydrochloride) were weighed in the mixing ratio shown in Table 1, passed through a 40-mesh sieve, and mixed in a hopper mixer.

[0075] (2) Tablet pressing.

[0076] 1.2 Accelerated stability study

[0077] Evaluation method and results: The tablets of Example 1-1 and Comparative Examples 1-2, 1-3, 1-4, 1-5, 1-6, and 1-7 were sealed with a composite film and placed under accelerated conditions of 40°C and 75% RH. The amounts of related substances were measured by HPLC (1260 Infinity, Agilent Technologies, Inc.) (see Table 2 for the detection method).

[0078] Table 2 HPLC detection method of related substances

[0079]

[0080] The results are shown in Table 3 below, which shows that the increase in the initial total amount of the related substances in Example 1-1 is better than that of the original tablets and Comparative Examples 1-2, 1-3, 1-4, 1-5, 1-6, and 1-7.

[0081] Table 3 Test results of related substances

[0082]

[0083] In Comparative Examples 1-3, the related substances increased significantly on day 0, indicating poor stability, and the stability investigation conditions were not further tested.

[0084] Example 2

[0085] Stability study of the formulation of a pharmaceutical composition without antioxidants and the preparations obtained therefrom

[0086] 2.1 Pharmaceutical compositions without antioxidants

[0087] Table 4 Prescription composition of pharmaceutical composition without antioxidant

[0088]

[0089]

[0090] Preparation method:

[0091] (1) Compound (I), direct-compressed mannitol M100, microcrystalline cellulose, pregelatinized starch, and magnesium stearate were weighed in the mixing ratio shown in Table 4, passed through a 40-mesh sieve, and added to a hopper mixer for mixing.

[0092] (2) Tablet pressing.

[0093] 2.2 Accelerated stability study

[0094] Evaluation methods and results: The tablets of each example, as well as the original tablets after peeling off the coating film, were sealed with a composite film and placed under accelerated conditions of 40°C and 75% RH. The amount of related substances was measured by HPLC (1260 Infinity, Agilent Technologies, Inc.) (detection method is the same as Table 2 above).

[0095] The results are shown in the table below, which shows that the increase from the initial total amount of related substances in the examples is superior to the original research (Daiichi Sankyo Co., Ltd.), and the total amount of related substances in the prescriptions of Examples 2-1 to 2-5 is <0.50% by 1 month.

[0096] Table 5 Test results of related substances

[0097]

[0098] 2.3 Light stability study

[0099] The compositions of Examples 1-1 to 1-7 were weighed and tableted according to the prescription, and the coating of the original tablets was removed and placed in a watch glass. The tablets were placed in a strong light test box with a light intensity of 4500±500 lux / h. The total luminosity was about 1.2 million lux for 13 days.

[0100] Table 6 shows that compared with the original tablets without coating, the total amount of related substances in the samples of each embodiment under light irradiation is also better.

[0101] Table 6 Detection results of related substances under 1.2 million lux illumination

[0102]

[0103]

[0104] Example 3

[0105] 3.1 Pharmaceutical compositions containing pregelatinized starch

[0106] Table 7 Prescription composition of the pharmaceutical composition containing pregelatinized starch

[0107]

[0108] Preparation method:

[0109] (1) Compound (I), D-mannitol, microcrystalline cellulose, pregelatinized starch, and magnesium stearate were weighed in the mixing ratio shown in Table 7, passed through a 40-mesh sieve, and mixed in a hopper mixer.

[0110] (2) Tablet pressing.

[0111] 3.2 Accelerated stability study

[0112] Evaluation method and results: The tablets of Examples 3-1, 3-2, and 3-3 were sealed with a composite film and placed under accelerated conditions of 40°C and 75% RH. The amount of related substances was measured by HPLC (1260 Infinity, Agilent Technologies, Inc.) (detection method is the same as Table 2 above).

[0113] The results are shown in Table 8 below, which shows that the increase in the initial total amount of the related substances in Examples 3-1, 3-2, and 3-3 is superior to that of the original tablets.

[0114] Table 8 Test results of relevant substances

[0115]

Claims

1. A pharmaceutical composition, characterized in that It comprises a compound as shown in formula (I), a filler, pregelatinized starch and a lubricant; The pharmaceutical composition does not include an antioxidant; 2. The pharmaceutical composition according to claim 1, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) The compound of formula (I) is present in an amount of 3-15% by weight of the pharmaceutical composition, preferably 6-12%, more preferably 8.5-10%, such as 8.75%, 8.95%, 8.96% or 9.16% by weight; (2) The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100; (3) The filler accounts for 75-90% by weight of the pharmaceutical composition, preferably 80-90%, such as 80.79%, 83.16%, 85.51%, 85.52%, 85.53% or 87.6%; (4) The lubricant is one or more selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl monostearate, poloxamer, sodium benzoate, sodium lauryl sulfate and talc, such as magnesium stearate; (5) The lubricant is present in an amount of 0.1-5% by weight of the pharmaceutical composition, preferably 0.6-1%, more preferably 0.7-0.85%, such as 0.77%, 0.79% or 0.81% by weight; The pharmaceutical composition described in (6) is a solid preparation, such as a tablet, and the tablet can be a plain tablet or a coated tablet.

3. The pharmaceutical composition according to claim 2, wherein The pharmaceutical composition satisfies one or more of the following conditions: (1) The directly compressible mannitol accounts for 35-90% by weight of the pharmaceutical composition, preferably 40-86%, such as 41.76%, 61.32%, 68.42%, 76.97% or 85.51%; (2) The microcrystalline cellulose accounts for 5-50% by weight of the pharmaceutical composition, preferably 5-45%, such as 8.55%, 14.74%, 15.92%, 17.11%, 26.28% or 41.76%; The pregelatinized starch described in (3) is 1-15% by weight of the pharmaceutical composition, preferably 2-10%, such as 2.43%, 4.74%, 4.75%, 6.95%, 7.11% or 9.48%.

4. The pharmaceutical composition according to claim 2, wherein The directly compressible mannitol accounts for 60-80% of the pharmaceutical composition by weight; And / or, the microcrystalline cellulose accounts for 5-30% by weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition comprises the following components by weight: 3-15% of the compound represented by formula (I), 75-90% of the filler, 1-15% of the pregelatinized starch and 0.1-5% of the lubricant; Preferably, the pharmaceutical composition comprises the following components by weight: 3-15% of the compound represented by formula (I), 60-80% of the directly compressible mannitol, 5-30% of the microcrystalline cellulose, 1-15% of the pregelatinized starch and 0.1-5% of the lubricant; More preferably, the pharmaceutical composition comprises the following components by weight: The compound represented by formula (I), the filler, the pregelatinized starch and the lubricant; The compound represented by formula (I) accounts for 8.75%, 8.95%, 8.96% or 9.16% of the pharmaceutical composition by weight; The filler accounts for 80.79%, 83.16%, 85.51%, 85.52%, 85.53% or 87.6% of the pharmaceutical composition by weight; The pregelatinized starch accounts for 2.43%, 4.74%, 4.75%, 6.95%, 7.11% or 9.48% of the pharmaceutical composition by weight; The lubricant accounts for 0.77%, 0.79% or 0.81% of the pharmaceutical composition by weight.

6. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition comprises the following components by weight: 3-15% of the compound represented by formula (I); 75-90% of the filler, wherein the filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100; 1-15% of the pregelatinized starch; 0.1-5% of the lubricant, wherein the lubricant is magnesium stearate; Preferably, the pharmaceutical composition comprises the following components by weight: The compound represented by formula (I), the filler, the pregelatinized starch and the lubricant; The compound represented by formula (I) accounts for 8.75%, 8.95%, 8.96% or 9.16% of the pharmaceutical composition by weight; The filler is directly compressible mannitol and / or microcrystalline cellulose; the directly compressible mannitol is preferably directly compressible mannitol M100; The filler accounts for 80.79%, 83.16%, 85.51%, 85.52%, 85.53% or 87.6% of the pharmaceutical composition by weight; The pregelatinized starch accounts for 2.43%, 4.74%, 4.75%, 6.95%, 7.11% or 9.48% of the pharmaceutical composition by weight; The lubricant is magnesium stearate; The lubricant is 0.77%, 0.79% or 0.81% by weight of the pharmaceutical composition; More preferably, the pharmaceutical composition comprises any combination of the following components by weight: Combination 1: 8.95% of the compound of formula (I), 68.42% of directly compressible mannitol M100, 17.11% of microcrystalline cellulose, 4.74% of pregelatinized starch, and 0.79% of magnesium stearate; Combination 2: 9.16% of the compound of formula (I), 61.32% of directly compressible mannitol M100, 26.28% of microcrystalline cellulose, 2.43% of pregelatinized starch, and 0.81% of magnesium stearate; Combination 3: 8.95% of the compound of formula (I), 76.97% of directly compressible mannitol M100, 8.55% of microcrystalline cellulose, 4.74% of pregelatinized starch, and 0.79% of magnesium stearate; Combination 4: 8.75% of the compound of formula (I), 41.76% of directly compressible mannitol M100, 41.76% of microcrystalline cellulose, 6.95% of pregelatinized starch, and 0.77% of magnesium stearate; Combination 5: 8.96% of the compound of formula (I), 85.51% of directly compressible mannitol M100, 4.75% of pregelatinized starch, and 0.79% of magnesium stearate; Combination 6: 8.95% of the compound of formula (I), 67.24% of directly compressible mannitol M100, 15.92% of microcrystalline cellulose, 7.11% of pregelatinized starch, and 0.79% of magnesium stearate; Combination 7: 8.95% of the compound of formula (I), 66.05% of directly compressible mannitol M100, 14.74% of microcrystalline cellulose, 9.48% of pregelatinized starch and 0.79% of magnesium stearate.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: directly compressing the components of the pharmaceutical composition into tablets.

8. The method for preparing the pharmaceutical composition according to claim 7, wherein: The preparation method of the pharmaceutical composition comprises the following steps: screening, mixing, and tableting the compound represented by formula (I) as described in claims 1-6, the directly compressible mannitol, the microcrystalline cellulose, the pregelatinized starch, and the lubricant; the screening can be through a 40-mesh sieve.

9. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a medicament for treating pain.

10. The use according to claim 9, characterized in that The pain is diabetic pain or post-herpetic neuralgia; And / or, the pain is chronic pain, which may be central neuropathic pain or peripheral neuropathic pain; the central neuropathic pain may be central neuropathic pain after spinal cord injury (SCI).

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