JP2021518423A - Oral coating tablet composition of lenalidomide - Google Patents

Abstract

Disclosed is an oral tablet composition containing lenalidomide, which is in the form of a tablet with further improved convenience, handleability, safety and the like. There is no teratogenic lenalidomide drug in the coating layer because the coating layer allows the internal drug to be separated from the handler. [Selection diagram] Fig. 1

Description

It relates to an oral tablet composition containing lenalidomide.

Multiple myeloma is a hematological malignancies characterized by abnormal differentiation and proliferation of plasma cells. These abnormal plasma cells are called myeloma cells. It mainly occurs in men (especially black men) and elderly people aged 65 and over, and in recent years, the incidence has been gradually increasing in South Korea. The main therapeutic agents for such multiple myeloma are bortezomib, thalidomide and lenalidomide.

Lenalidomide was developed by Celgene as an oral capsule formulation and is commercialized at doses of 25, 20, 15, 10, 7.5, 5, 2.5 mg.

Since lenalidomide is also a derivative of thalidomide, it cannot be prescribed to pregnant women. Therefore, lenalidomide was marketed as a hard capsule so as not to cause damage due to an unintended outflow of the drug. That is, the outflow and disappearance of the drug were controlled by filling the thick hard capsule with the drug in the same manner as thalidomide.

The brand name in South Korea is Lebramide® Capsules, which contains lenalidomide hemihydrate. Rebramide® capsule, which is a rigid capsule preparation, is filled in No. 0 capsule in all cases of 25, 20, 15 and 10 mg preparations, and its long axis is about 2.17 cm, which is quite long and bulky. ing. Therefore, patients, especially elderly patients, may find it inconvenient to take. In addition, capsules may stick to the throat and esophagus during swallowing, even when taken with water. In this case, the capsule may not be removed from the site, even if the patient drinks a large amount of water. If the drug is accidentally released from the capsule, it can cause pain and, in some cases, inflammation. Therefore, if a tablet form with a short length and a small volume is developed, the problem caused by the inconvenient and bulky capsule can be solved, whereby the patient can take the medicine more easily. be able to. That is, the drawbacks of capsules can be overcome.

In the late 1950s and 1960s, thalidomide was used as an anti-morning sickness agent in pregnant women, but there was a tragic event in which tens of thousands of malformed children were born worldwide due to unexpected teratogenic side effects. .. Lenalidomide, which is similar to thalidomide, has teratogenic side effects and is therefore prohibited from being administered or treated to pregnant women, women of childbearing age or women of childbearing potential. In order to prevent such side effects, it is believed that a thick gelatin capsule surrounds the drug during the manufacture of the capsule to achieve safe shielding. However, in the case of tablets (particularly uncoated tablets), the drug is directly present on the surface of the tablet and can be exposed to unrelated handlers. If the patient takes the split amount along the split line of the tablet, or if it breaks when removed from the blister pack due to fragility, or if it collapses due to poor wear, the handler and surrounding people There is a risk of drug exposure.

In addition, the dosage form of tablets containing lenalidomide requires the drug to be designed and manufactured to exhibit the same drug release rate and release pattern as clinically validated commercially available capsules.

An object of the present invention is to change the dosage form of a commercially available hard capsule lenalidomide preparation to a tablet, the length is short, it is not bulky, it is easy to take, and the coating base is appropriately selected and the coating thickness is appropriately selected. By selecting, the tablet composition can separate the internal drug from the handler and prevent the drug from being released during the coating process by completely wrapping over a certain thickness of the entire tablet. Is to provide.

Another object of the present invention is that the dissolution pattern is equivalent to that in capsules, which not only shows physicochemical equivalence in comparative dissolution tests, but also in in vivo tests of laboratory animals and bioequivalence tests. The purpose is to provide a tablet composition showing equivalence.

Therefore, the present invention has the same pharmacological efficacy and effect as the commercially available capsule preparation, and has been further developed to improve the appearance, convenience of administration and handling, ease of manufacture, safety and the like. A tablet composition and a method for producing the same are provided.

Meaning of Terms Unless otherwise stated, some terms used herein may be defined as follows.

In the context, "contains" or "contains" means to include any component (or component) without any special limitation, unless explicitly indicated otherwise, and other components (contains). Or components) should not be interpreted as excluding.

Further, "lenalidomide" may be a lenalidomide base (salt-free base), a pharmaceutically acceptable salt thereof or an isomer thereof, or a mixture thereof. Further, in each case, it may be various hydrates, and in each case, it may be in various crystalline forms. For example, it may be various hydrates such as renalidemid anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or various solvates, or a mixture thereof.

In order to solve the above problems, the present invention provides an uncoated tablet containing lenalidomide and one or more pharmaceutically acceptable carriers as an active ingredient; and an oral tablet composition containing a coating layer for coating the tablet; offer. Here, the carrier can contain a diluent, a disintegrant, and a lubricant.

In the oral tablet composition of the present invention, since the surface of the uncoated tablet is coated with a coating base, the drug inside can be separated from the tablet handler, and the drug may be released during the coating process. Long.

In addition, the present invention is used to lock with an appropriate tableting pressure so as to have an appropriate range of hardness and to show the same dissolution pattern as a commercially available capsule preparation.

In one embodiment, the diluent may be selected from the group consisting of sugars, sugar alcohols, celluloses, starches, inorganic salts, and mixtures thereof; the disintegrants are swelling disintegrants, wet disintegrants, And may be selected from the group consisting of mixtures thereof; the lubricant may be selected from one or more groups consisting of soluble lubricants, insoluble lubricants and mixtures thereof.

In one embodiment, the coating layer of the oral tablet composition may be a single layer or a double layer or more.

In one embodiment, the oral tablet composition comprises 0.5 to 200 parts by weight of lenalidomide relative diluent, 0.02 to 10 parts by weight of disintegrant and / or 0.005 to 3.5 parts by weight of lubricant. Can include parts.

In the present invention, the diluent is, for example, lactose (anhydrous or hydrate, for example, monohydrate), cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, carbonate. Calcium, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, One selected from the group consisting of kaolin, magnesium carbonate, magnesium oxide, mannitol, martitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose, maltodextrin, dextrin, dextrin, and mixtures thereof. The above may be, but the present invention is not limited to these. Preferably, lactose, microcrystalline cellulose, mannitol, starch, or a mixture thereof may be selected. Most preferably, a mixture of lactose and microcrystalline cellulose may be selected, and the diluent may also act as a binder.

In one embodiment, the diluent is used in an amount of, for example, 2 to 50 parts by weight, or 2 to 45 parts by weight, or 5 to 30 parts by weight, or 10 to 20 parts by weight, based on 1 part by weight of lenalidomide. You may. If the amount of diluent used is much less than the above range, it is difficult to produce tablets. On the other hand, if the amount of the diluent is much larger than the above range, the concentration of the drug may be low, which may cause a problem in ensuring the uniformity of the contents during tablet production.

In the present invention, the disintegrant may be selected from the group consisting of, for example, starch, cellulose, crosslinked polymers, gums, polysaccharides, and mixtures thereof. For example, croscarmellose sodium (CrosCMC-Na), carboxymethyl cellulose, crospovidone (crosslinked polyvinylpyrrolidone), L-HPC (low substitution hydroxypropyl cellulose), starch (wheat, rice, corn or potato starch), carboxymethyl starch. It may be one or more selected from the group consisting of sodium, sodium starch glycolate, alginic acid, sodium carboxymethyl cellulose, agar, xylan, gellan gum, xanthan gum, partially hydrolyzed starch, and mixtures thereof. Not limited to. Preferably, it may be croscarmellose sodium, crospovidone, L-HPC, sodium starch glycolate. More preferably, it may be croscarmellose sodium.

In one embodiment, the disintegrant is such that the disintegrant is, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.2 to 1.5 parts by weight, based on 1 part by weight of lenalidomide. It may be used in an amount of 0.1 to 1 part by weight. If the amount of the disintegrant used is much smaller than the above range, the delay in the elution rate may become a problem due to the delay in the disintegration rate. On the other hand, if the amount of the disintegrant is much larger than the above range, there may be a problem in productivity such as poor compression or poor coating.

In the present invention, the lubricant is a concept that includes a lubricant, an anti-adhesive agent, and a flow accelerator. For example, lubricants include magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, starch (wheat, rice, corn or potato starch), talc, highly dispersed (colloidal) silica, Magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, monostearate It may be, but is not limited to, one or more selected from the group consisting of polyoxyethylene acid acid, glyceryl triacetate, sucrose monolaurate, and mixtures thereof. The lubricant may preferably be magnesium stearate, stearic acid, or highly dispersed (colloidal) silica. More preferably, it may be magnesium stearate.

In one embodiment, the lubricant is, for example, 0.05 to 10 parts by weight, or 0.1 to 5 parts by weight, or 0.1 to 1 part by weight, or 0.1 to 1 part by weight, based on 1 part by weight of lenalidomide. It may be used in an amount of 0.5 parts by weight. If the amount of lubricant used is excessively smaller than the above-mentioned range, there may be a problem in productivity such as locking failure, and conversely, if it is excessively larger than the above-mentioned range, there may be a problem in elution delay or productivity.

In the present invention, the coating base may be an aqueous polymer, for example, a polymer of hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, acrylic acid and a salt thereof. , Polymethacrylate, poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate) copolymer (eg, Eudragit® E, Evonik), carboxymethylcellulose (sodium and calcium salts), ethylcellulose, Methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), L-HPC (low substitution HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (eg, Collidon) (registered) It may be one or more selected from the group consisting of (trademark) VA64, manufactured by BASF), gelatin, guar gum, partially hydrolyzed starch, alginate, xanthane, and a mixture thereof, but is not limited thereto. Preferably, the coating base is a hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer ( For example, it may be Eudragit® E, Evonik).

In one embodiment, the coating layer is, for example, 0.05 to 10 parts by weight, or 0.1 to 3 parts by weight, or more than 0.1 to less than 3 or 0.2, based on 1 part by weight of renalidemid. It may be used in an amount of ~ 2.5 parts by weight or 0.5 to 2 parts by weight. If the amount of the coating base used is much smaller than the above range, there is a problem that the entire uncoated tablet is not covered with the coating base. On the other hand, if the amount of the coating base used is much larger than the above range, the dissolution rate may be excessively delayed.

The film thickness of the coating layer after cutting the tablet in half can be measured by a scanning electron microscope (SEM) or the like. At this time, it is preferable that the entire surface of the tablets is uniformly coated with a constant film thickness, and the average film thickness can be obtained by measuring and averaging five or more tablets. When observing the cross section, the average film thickness of the coating layer may be 1 μm or more and 300 μm or less. It may be more preferably 10 μm or more and 200 μm or less, further preferably 15 μm or more and 150 μm or less, and most preferably 20 μm or more and 100 μm or less. If the average film thickness of the coating layer is thinner than the above range, it becomes difficult to uniformly coat the entire tablet, and dust may be generated during handling. If the average film thickness of the coating layer is thicker than the above range, the desired purpose may not be achieved due to reasons such as elution delay and excessive treatment time.

When the coating layer is formed as a single layer, one or more kinds of coating bases may be mixed and used, or the entire tablet may be coated with a sufficient amount of the coating base to form the coating layer. The coating layer is preferably two or more layers. For example, when coating with more than two layers, each layer may be made with different coating bases to protect the tablets from exposure to drugs, moisture, oxidation and the like. When double-coated, the protection from the external environment can be increased. Primary coating bases that come into direct contact with the uncoated tablets include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinylacetate copolymers (eg, Kollidon). ) (Registered trademark) VA64, manufactured by BASF), polyethylene glycol (PEG), sodium carboxymethyl cellulose (Na-CMC) or a combination thereof, and a secondary coating base further coated on the primary coating. Examples include polyvinyl alcohol (PVA), macrogol polyvinyl alcohol graft copolymer, poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer (eg, Eudragit® E, ebonic), gelatin. , Gua gum, partially hydrolyzed starch, alginate, xanthan or a combination thereof. In one embodiment, preferably a primary coating with hydroxypropyl methylcellulose (HPMC) is applied to form a barrier to the drug, followed by a secondary coating with a macrogol polyvinyl alcohol graft polymer to finally be applied. It is preferable to form two coating layers. In one embodiment, better function is achieved by performing a primary coating with hydroxypropyl methylcellulose (HPMC) to form a barrier against the drug and then a secondary coating with polyvinyl alcohol (PVA) to form a moisture-proof barrier. It is possible to form a two-layer coating layer having, but is not limited to this.

Careful selection of the type and composition of the solvent used in the production of the coating solution is required to prevent the drug from being instantaneously dissolved by the coating solution during coating and contained in the coating layer. Further, as the coating condition, it is necessary to establish the condition that the coating liquid can be quickly dried after coating the uncoated tablet. The coating solvent may be, but is not limited to, ethanol, methanol, acetone, acetonitrile, tetrahydrofuran, hexane, methylene chloride, isopropyl alcohol, water, etc., or a mixed solvent thereof. Preferably, ethanol, water, or a mixture thereof can be used. More preferably, a mixture of ethanol and water, a mixture of methylene chloride and ethanol, or a mixture of isopropyl alcohol and ethanol can be used to form the primary coating, and then water can be used to form the secondary coating.

In the process of manufacturing coated tablets as described above, various additional biology for the purpose of further improving coating efficiency, drug stability, appearance, color, protection, maintenance, binding, performance, manufacturing method, etc. Inactive ingredients can be used.

In one embodiment, biologically inert components that may be further included in the coating layer are plasticizers, lubricants, colorants, flavoring agents, surfactants, stabilizers, antioxidants, etc. It may be one or more selected from the group consisting of foaming agents, defoaming agents, paraffin, wax and the like.

The plasticizers that may be further included in the coating layer include, for example, triethylcitrate, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, tributyl citrate, triethyl acetylcitrate, triethyl acetylcitrate, It may be, but is not limited to, one or more selected from the group consisting of propylene glycol, triacetin, polyethylene glycol, cetyl alcohol, stearyl alcohol, and cetostearyl alcohol.

The plasticizer is 100% by weight or less (for example, 0 to 100% by weight or 0.1 to 100% by weight), specifically, when the dry weight of all the polymers used in each coating layer is 100% by weight. It is contained in an amount of 50% by weight or less (for example, 0 to 50% by weight or 0.1 to 50% by weight), more specifically 30% by weight or less (for example, 0 to 30% by weight or 0.1 to 30% by weight). It may be, but it is not limited to this.

The lubricants that may be further included in the coating layer include, for example, magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, starch (wheat, rice, corn or potato starch), talc. , Highly dispersed (colloidal) silica, magnesium oxide, magnesium carbonate, glyceryl behate, gluceryl monostearate, silicon dioxide, calcium silicate, magnesium silicate, and one or more selected from the group consisting of mixtures thereof. If there is, it is not limited to this. The lubricant is contained in an amount of 100% by weight or less (for example, 0 to 100% by weight or 0.1 to 100% by weight) when the total dry weight of the polymer used for each coating layer is 100% by weight. It may be, but it is not limited to this.

In the tablet composition of the present invention, lenalidomide and one or more pharmaceutically acceptable carriers are mixed as an active ingredient, and the mixture is compressed to produce a pre-coating tablet (uncoated tablet), and then the uncoated tablet is prepared. Provided is a method for producing an oral tablet composition of the present invention, which comprises coating the surface with a coating base.

Specifically, the tablets of the present invention are manufactured in the order of granulation, mixing, tableting, and coating after the nominal amount of the raw material component, or after the nominal amount of the raw material component, mixing, tableting (direct tableting), It can be manufactured in the order of coating. Granulation can be performed by a method such as dry granules or wet granules.

In one embodiment, when granulated with wet granules, the granules are obtained by making a binder solution, forming the granules from a mixture such as a diluent with the drug, sieving and drying. Then, the remaining components were mixed and then compressed. The binder solution is a water-soluble polymer such as hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), L-HPC (low substitution HPC), polyvinylpyrrolidone (PVP), and the like. Vinylpyrrolidone-vinylacetate copolymer (eg, Kollidon® VA64, manufactured by BASF), or sugars, sugar alcohols, such as sucrose, sorbitol, maltitol, xylitol, erythritol, etc. in water or ethanol. Alternatively, it can be produced by dissolving it in a mixed solution of these.

In one embodiment, when granulated with dry granules, a mixture of drug, diluent and binder was pressed and screened using a roller compactor or the like. Then, the remaining components were mixed and then compressed.

Direct compression instead of granulation has the advantage of simplifying the process because the ingredients are mixed and compressed immediately after the nominal amount of the raw material. Protective equipment must be worn during the manufacturing process due to the teratogenic side effects of the drug itself. Pregnant and potentially pregnant women should be excluded. In addition, it may be preferable, but not limited to, to use direct compression, which minimizes worker exposure to the drug.

The hardness of the uncoated tablet varies depending on the shape, weight and size of the tablet, but the maximum average hardness of 300 N and the minimum average hardness of 20 N are preferable. Preferably, the maximum average hardness is 250 N and the minimum average hardness is 30 N. More preferably, the maximum average hardness is 230N and the minimum average hardness is 35N, particularly 40N to 200N. If the hardness of the uncoated tablet is much higher than the above range, the release of the drug may be delayed due to the delayed disintegration. On the other hand, if the hardness of the uncoated tablet is much lower than the above range, the tablet may become brittle and crack during coating, transportation, storage, and ingestion.

The hardness means a value measured on the long axis in the case of a rectangular tablet, and means the average hardness of 6 randomly selected tablets.

In the present invention, the disintegration time of the uncoated tablet is one of the important factors that can determine the release time of the drug. Therefore, it is necessary to have an appropriate hardness by compressing with an appropriate pressure during the tableting process. As a result, the tablets can have the desired disintegration time, which can be a factor in determining the dissolution pattern of the drug, in addition to the coating amount of the coating base in the coating process. Since the elution pattern affects absorption in the body, it may be important to set the appropriate disintegration time by providing the appropriate hardness with the appropriate tableting pressure. In addition, the drug elution pattern should be the same, even at different doses. That is, the disintegration time should be the same for all tablets with different doses.

The disintegration time was measured in No. 10 (KPX) of the general test method of the Korean Pharmacopoeia in the pH 1.2 buffer solution, which is the first test solution. 17 It can be measured according to the disintegration test method. Disintegration time is determined by measuring and averaging 6 tablets. In one embodiment, the average disintegration time of the uncoated tablet is 1 to 20 minutes. It is preferably 1 minute 30 seconds to 15 minutes, more preferably 2 minutes to 10 minutes, further preferably 2 minutes 30 seconds to 8 minutes, even more preferably 3 minutes to 6 minutes, and most preferably 3 minutes 30 seconds to 5 minutes. It is 30 seconds. In the present invention, the coating layer formed on the uncoated tablet may be a single layer, two or more layers, and more preferably two or more layers.

The solvent for coating can vary. For example, in the case of HPMC coating, the solvent may have absolute ethanol and water in a ratio of 2: 8 to 8: 2, or water alone. Further, for example, water can be used alone as a solvent for coating PVA. All of these solvents volatilize during the coating process and are virtually non-residual in the final product.

The tablet may further contain various additives in order to improve the physical properties, manufacturability, compressibility, appearance, taste and / or stability of the drug, etc. of the tablet. Such additives include, for example, stabilizers, solubilizers, sweeteners, flavoring agents, pigments, wetting agents, fillers, stabilizers, surfactants, lubricants, solubilizers, buffers, etc. Sweeteners, adsorbents, flavoring agents, binders, suspending agents, hardening agents, antioxidants, brighteners, flavoring agents, flavoring agents, pigments, coating agents, wetting agents, wetting regulators, fillers, erasers Foaming agents, cooling agents, chewing agents, antistatic agents, coloring agents, sugar coating agents, isotonic agents, softening agents, emulsifiers, pressure-sensitive agents, thickeners, foaming agents, pH regulators, excipients, dispersions Includes, but is not limited to, agents, disintegrants, waterproofing agents, preservatives, preservatives, solubilizers, solvents, fluidizing agents, etc., but optionally added as long as pharmaceutically acceptable. Agents can be used.

The coated tablet of the present invention can exhibit an dissolution rate equivalent to the dissolution rate of the comparative preparation produced in capsules. In particular, the initial elution rate at 2.5 minutes, 5 minutes, 10 minutes, 15 minutes, etc. is important under acidic conditions such as a buffer solution having a pH of 1.2. Lenalidomide has a pH-dependent solubility and will affect the solubility and absorption of the drug depending on where it is disintegrated in the body. In particular, since the drug is highly soluble at low pH, it can be said that the release pattern in the stomach after administration is the main factor that determines the drug absorption pattern. Therefore, adjusting the disintegration time and dissolution pattern of the pharmaceutical product to be similar to that of the control drug is an important requirement for ensuring the same drug absorption pattern.

The dissolution test is No. 1 among the general test methods in the 10th edition (KPX) of the Korean Pharmacopoeia. According to the 35 dissolution test method, the paddle method, which is the second method, is carried out at 37 ° C. and 50 rpm. The average dissolution rate at a time point can be obtained by testing each of the 6 tablets and measuring their dissolution rate at each time point by HPLC.

The tablet composition containing lenalidomide disclosed in the present invention can be usefully used as a composition in the form of a tablet with further improved convenience, handleability, safety and the like. In particular, since the internal drug and the handler can be separated by the coating layer, the teratogenic lenalidomide drug is not released to the coating layer, so that the drug does not come into contact with the coating layer even if it comes into contact with the coating layer. Further, the initial elution rate such as 2.5 minutes, 5 minutes, 10 minutes, and 15 minutes under the same acidic conditions as the buffer solution of pH 1.2 is important, but the tablet composition according to the present invention has been conventionally commercially available. It showed the same pattern as the elution of capsules.

It is a graph which showed the result of the elution comparative test of Example 2 and Comparative Example 1 with the eluate of pH 1.2. It is a graph which showed the result of the elution comparison test of Example 2 and Comparative Example 1 with the eluate of pH 4.0. It is a graph which showed the result of the elution comparative test with the eluate of water of Example 2 and Comparative Example 1. It is a graph which showed the result of the elution comparative test of Example 2 and Comparative Example 1 with the eluate of pH 6.8. It is a graph which showed the result of the elution comparative test of Example 3 and Comparative Example 1 with the eluate of pH 1.2. It is a graph which showed the result of the elution comparison test of Example 3 and Comparative Example 1 with the eluate of pH 4.0. It is a graph which showed the result of the elution comparative test with the eluate of water of Example 3 and Comparative Example 1. It is a graph which showed the result of the elution comparative test of Example 3 and Comparative Example 1 with the eluate of pH 6.8. It is a figure which showed the result of FT-IR analysis of the surface of the tablet obtained in Example 1.

The present invention will be described in more detail with reference to the following examples. However, these examples are for the purpose of exemplifying the present invention only, and the scope of the present invention is not limited to these examples.

Example 1 and Comparative Example 1
The tablets of Example 1 were produced according to the following production method with the components and contents as shown in Table 1 below. As Comparative Example 1, commercially available Rebramide 25 mg capsules were used.

<Manufacturing of uncoated locks>
Lenalidomide and lactose anhydrous were sieved and mixed. Then, microcrystalline cellulose, sodium croscarmellose and magnesium stearate were sieved and finally mixed. The mixture was compressed with a rectangular punch. The hardness of the uncoated tablet was 120 N.

<Coating of uncoated lock>
The tablets produced above were double-coated with two kinds of coating agents in a total amount of 7.5% (w / w) with respect to the uncoated tablets for the purpose of drug shielding. After primary coating (2.5% (w / w)) with Opadry® containing HPMC as the main component, secondary coating (5% (5% (5%)) with Opadry® containing PVA as the main component. w / w)) was performed.

Comparative Example 2
The tablets of Comparative Example 2 were produced according to the following production method with the components and contents as shown in Table 2 below.

<Manufacturing of uncoated locks>
Lenalidomide and lactose anhydrous were sieved and mixed. Then, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, AEROSIL and stearic acid were sieved and finally mixed. The mixture was compressed with a rectangular punch. The hardness of the uncoated tablet was 15N.

<Coating of uncoated lock>
The manufactured uncoated lock was double-coated in the same manner as in the uncoated tablet of Example 1.

Example 2
The tablets of Example 2 were produced according to the following production method with the components and contents as shown in Table 3 below.

<Manufacturing of uncoated locks>
Lenalidomide and spray-dried mannitol were sieved and mixed. Then, rice crystalline cellulose, sodium starch glycolate, and calcium stearate were sieved and finally mixed. The mixture was compressed with a rectangular punch. The hardness of the uncoated tablet was 143N.

<Coating of uncoated lock>
The tablets produced above were double-coated with two kinds of coating agents in a total amount of 7.5% (w / w) with respect to the uncoated tablets for the purpose of drug shielding. After primary coating (2.5% (w / w)) with Opadry® containing HPMC as the main component, secondary coating (5% (5% (5%)) with Opadry® containing PVA as the main component. w / w)) was performed.

Example 3
<Manufacturing of uncoated locks>
The uncoated tablet was produced by the same components, contents and production method as in the production of the uncoated tablet of Example 2 except that the hardness of the uncoated tablet was compressed at 155 N.

<Coating of uncoated lock>
The tablets produced above were double-coated with two kinds of coating agents in a total amount of 7.5% (w / w) with respect to the uncoated tablets for the purpose of drug shielding. After primary coating (2.5% (w / w)) with Opadry® containing HPMC as the main component, secondary coating (5% (5% (5%)) with Opadry® containing PVA as the main component. w / w)) was performed.

Example 4
<Manufacturing of uncoated locks>
The uncoated tablet was produced by the same components, contents and production method as in the production of the uncoated tablet of Example 2 except that the hardness of the uncoated tablet was compressed with 163 N.

<Coating of uncoated lock>
The tablets produced above were double-coated with two kinds of coating agents in a total amount of 7.5% (w / w) with respect to the uncoated tablets for the purpose of drug shielding. After primary coating (2.5% (w / w)) with Opadry® containing HPMC as the main component, secondary coating (5% (5% (5%)) with Opadry® containing PVA as the main component. w / w)) was performed.

Test Example 1: Measurement of abrasion degree The abrasion degree is measured by the method described in the abrasion degree test item of 1216 tablets of the United States Pharmacopeia using a Pharmacopoeia wear rate tester (Pharmatest friability tester) for 10 tablets. The differences between the uncoated tablets and the coated tablets with respect to Examples 1 to 4 and Comparative Example 2 are shown in Table 4 below (measurement time = 4 minutes).

In a general production process, the degree of abrasion must be controlled to 0.2% or less, and due to the characteristics of the teratogenic active ingredient, the degree of abrasion should be controlled to be low for the safety of workers. Is preferable.

Test Example 2: Disintegration test According to the disintegration test method of the 10th edition of the Korean Pharmacopoeia, disintegration tests of Examples 1 to 4 and Comparative Examples 1 and 2 were performed in a pH 1.2 solution (n = 3), and the results were obtained. It is shown in Table 5 below.

As a result of the experiment, all the compositions of Examples 1 to 4 showed a preferable disintegration time of 210 seconds to 350 seconds with that of Comparative Example 1 (control agent).

Test Example 3: Comparative dissolution Using Example 2 and Comparative Example 1 (Rebramid (registered trademark) capsule formulation), pH 1.2 and pH 4.0 according to the dissolution test method in the general test method of the 8th edition of the Korean Pharmacopoeia. The elution rate was measured over time in water at pH 6.8.
The elution rate was measured by liquid chromatography using the test solution collected at each elution time. The elution files are shown in FIGS. 1 to 4.
<Elution conditions>
Dissolution test equipment: Paddle method of the Korean Pharmacopoeia dissolution test method Test solution: pH1.2, pH4.0, pH6.8, water Rotation speed: 50 rpm
Temperature: 37 ° C
Dissolution reference time:
5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes (pH 1.2, pH 4.0)
5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes (pH 6.8, water)
Analytical method: HPLC analytical method

As a result of the experiment, the composition of Example 2 was about the same as that of Comparative Example 1 (control drug) (the dissolution rate of the control drug was 60%, and the difference in dissolution rate from the test drug at 85% was within 15%). The dissolution pattern was shown.

Test Example 4: Comparative dissolution Using Comparative Example 3 and Comparative Example 1 (Rebramid (registered trademark) capsule preparation), a comparative dissolution test was performed in the same manner as in Test Example 3. The elution rate was measured by liquid chromatography using the test solution collected at each elution time. The elution file is shown in FIGS. 5 to 8.
As a result of the experiment, the composition of Example 3 showed an elution pattern comparable to that of Comparative Example 1 (control drug).

Test Example 5: Non-clinical study To compare the test substance lenalidomide tablets (25 mg dose) produced in Examples 2 and 3 with the comparative substance levramide® capsules (Celgene, 25 mg dose). After oral administration to celgene dogs, the concentration of lenalidomide in the blood was analyzed to confirm the pharmacokinetic profile.
The test animals were divided into two groups after fasting for 24 hours before the start of the experiment, and the test substance and the comparative substance were orally administered together with water on an empty stomach. After the test, blood was collected at predetermined intervals for up to 24 hours, and after a washout period of 2 weeks, a cross test was performed. Plasma was isolated from the collected blood samples and cryopreserved. The sample was analyzed by LC / MS / MS apparatus to obtain blood concentration. AUC and Cmax were calculated from the data, and the results are shown in Table 6 below.

As a result of the experiment, all of Examples 2 and 3 were evaluated to have bioequivalence with respect to Comparative Example 1.

Test Example 6: FT-IR
In order to confirm whether the active ingredient lenalidomide component is detected from the surface of the double-coated tablet, FT-IR analysis was performed on the surface of lenalidomide and the coated tablet of Example 1 and the inside of the tablet. FIG. 9 shows the results of FT-IR analysis on the surface of the coated lock. This confirmed that the lenalidomide component was detected inside the tablet but not on the surface.

Test Example 7: Physical characteristics of tablets according to coating rate Tablets were produced in which the uncoated tablets of Example 1 were coated with Opadry (PVA-based) at different ratios of 5 to 32% of the weight of the uncoated tablets. The final coating rate was calculated by the amount of weight increase after coating as compared with the tablet weight.

<Disintegration time due to coating rate>
A disintegration test was performed in a pH 1.2 solution (n = 3) on the tablets for each coating produced according to the disintegration test method of the 10th edition of the Korean Pharmacopoeia, and the results are shown in Table 7 below.

<Film thickness of coating layer according to coating rate>
For the average film thickness of the coating layer, after cutting the tablet in half, observe the average thickness of the coating layer with a scanning electron microscope (SEM), record the average of the five film thickness values, and see Table 7 below. Indicated.

As a result of the test, it was found that the disintegration time was suitable when the coating rate was 5% to 13%.

Test Example 8: Physical characteristics of tablets based on coating agent content Based on the components, content and production method of Example 2, the coating agent content ratio was measured as shown in Table 8 below, and the disintegration rate and the degree of abrasion were measured.

It was confirmed that when the coating agent was coated with 0.1 part by weight with respect to 1 part by weight of the main component, there was almost no difference from the uncoated tablet before coating. Therefore, it can be said that there is almost no coating effect.
Further, when the coating agent is coated in 3 parts by weight with respect to 1 part by weight of the main component, there is a problem that the disintegration time becomes excessively long.
When the degree of abrasion was 0.5% or less and the disintegration time was 210 to 350 seconds (3 minutes 30 seconds to 5 minutes), it was judged to be suitable.

Test example 9. Bioequivalence test of lenalidomide To compare the test substance lenalidomide tablets (25 mg dose) produced in Example 1 with the Lebramide® capsules (Celgene, 25 mg dose) of Comparative Example 1, 41 healthy individuals A bioequivalence test was conducted on male volunteers.
The subjects were divided into two groups, the test substance and the comparative substance were given with water under fasting, and blood was collected at predetermined intervals for up to 24 hours. Two weeks later, different groups were tested for the same drug. Blood was collected, plasma was separated from the collected blood samples, and they were cryopreserved. The sample was analyzed by LC / MS / MS apparatus to obtain blood concentration. AUC and Cmax were calculated from the data, and the results are shown in Table 9 below.

From the above data, the tablets of Example 1 were evaluated to be bioequivalent when compared to the dosage forms of Comparative Example 1.

Claims (8)

Unlocked tablets containing lenalidomide, diluents, disintegrants and lubricants; and coating layers coating the uncoated tablets;
Oral tablet composition containing. The oral tablet composition according to claim 1, wherein the coating layer is a single layer or a double layer or more. The coating base of the coating layer is polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, polyvinyl alcohol, macrogol polyvinyl alcohol. Graft copolymer, polymer of acrylic acid and its salts, polymethacrylate, poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate) copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, guar gum, partial The oral tablet composition according to claim 2, wherein the oral tablet composition is one or more selected from the group consisting of starch, alginate, xanthane, and a mixture thereof that have been hydrolyzed. The coating layer is a bilayer and
The primary coating layer in contact with the uncoated tablet contains hydroxypropyl methylcellulose,
The oral tablet composition according to claim 3, wherein the secondary coating layer in contact with the outside contains polyvinyl alcohol. The oral tablet composition according to any one of claims 1 to 4, wherein the weight of the coating layer is 0.2 to 2.5 parts by weight with respect to 1 part by weight of lenalidomide. The oral tablet composition according to any one of claims 1 to 4, wherein the coating layer has a film thickness of 15 μm to 150 μm. The oral tablet composition according to any one of claims 1 to 4, wherein the uncoated tablet has a hardness of 20N to 300N. Diluters include lactose, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, starch, gelatinized starch, calcium carbonate, cyclodextrin, calcium sulfate, calcium silicate, magnesium carbonate, dicalcium phosphate, Tricalcium phosphate, magnesium trisilicate, potassium chloride, sodium chloride, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, mannitol, martitol, sorbitol, xylitol, lactose, dextrin , Martose, sucrose, glucose, fructose, malt dextrin, dextrin, dextrin and mixtures thereof.
Disintegrants include croscarmellose sodium, carboxymethyl cellulose, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium carboxymethyl starch, sodium starch glycolate, alginic acid, sodium carboxymethyl cellulose, agar, xylan, gellan gum, xanthan gum, partial One or more selected from the group consisting of starch hydrolyzed in and a mixture thereof.
Lubricants include magnesium stearate, fumaric acid, stearic acid, calcium stearate, sodium stearyl fumarate, sucrose fatty acid ester, starch, talc, highly dispersed silica, magnesium oxide, magnesium carbonate, glyceryl behenate, glyceryl monostearate, Silicon dioxide, calcium silicate, magnesium silicate, hardened vegetable oil, hard liquid paraffin, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, polyoxyethylene monostearate, glyceryl triacetate, sucrose monolaurate and others. The oral tablet composition according to any one of claims 1 to 4, wherein one or more of them are selected from the group consisting of a mixture of.

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