ERLOTINIB NANOPARTICLE, MANUFACTURING METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING ERLOTINIB NANOPARTICLE

In the present invention hereinafter described specifically as follows.

In the present invention implies deionized water (deionized water (DI)) 0 the terms "nanoparticles". 5 mg/ml concentration in 30 minutes to 37 °C (active ingredient reference) can be dispersed in an manner been rapidly DLS (Dynamic light scattering) when measured, D90 value 5000 nm hereinafter, preferably 2000 nm hereinafter, more preferably 1000 nm hereinafter, more preferably 900 nm hereinafter, more preferably 800 nm hereinafter, more preferably 700 nm hereinafter, more preferably 600 nm hereinafter, more preferably 500 nm hereinafter phosphor particles and of the graphics, wherein particles of D90 value is, its value is not less than 90% or more of particles having a particle size weight defined particle size distribution. D90 is simplified and one free of a top limit number of nanoparticles, said nanoparticles D90 value is, for example, at least 50 nm, 100 nm or more, or 200 nm or more, or can be a 300 nm or more, is not limited.

In the present invention, said excipients is simplified and one free number number, nanoparticles of active substances according to the available number of excipients known publicly known, or even if a novel nanoparticles of active substances according to the present invention can be applied even if what is available.

Part protrudes from the body of the present invention, said biocompatible polymer excipients include number, number surfactants, selected from saccharide and combinations thereof can be employed.

Said biocompatible polymer particular examples, but not limited to, gelatin (gelatin), car number in (casein), dextran (dextran), gum arabic (gum acacia), [...] rubber (tragacanth), polyethylene glycol (polyethylene glycols), carboxymethyl cellulose (carboxymethylcellulose), hydroxypropyl cellulose (hydroxypropylcellulose), hydroxypropyl methyl cellulose (hydroxypropyl methylcellulose), with three rules five [cu methyl (methyl cellulose), hydroxy (hydroxyethyl cellulose) hour ethyl with the rule which it will count five [cu, hydroxypropyl methyl cellulose phthalate (hydroxypropyl methyl cellulose phthalate), amorphous cellulose (noncrystalline cellulose), polyvinyl alcohol (polyvinyl alcohol), polyvinyl pyrrolidone (polyvinypyrrolidone), Poloxamer flocked (poloxamers), type [tu act (eudragit^® ), By lighting element (lysozyme), and combinations thereof selected from albumin (albumin) is cited.

Said specific number surfactants include, but not limited to, pyridinium chloride (cetyl pyridinium chloride) triacetyl, phospholipid (phospholipids), fatty acid (fatty acid), it cuts well the nose [ni bud chloride (benzalkonium chloride), calcium stearate (calcium stearate), glycerin fatty acid ester (glycerin esters of fatty acid), fatty alcohol (fatty alcohol), dibenzothiazyl disulfide e crow goal (cetomacrogol), a polyoxyethylene alkyl ether (polyoxyethylene alkyl ethers), sorbitan ester (sorbitan esters), a polyoxyethylene castor oil derivatives (polyoxyethylene castor oil derivatives), of polyoxyethylene sorbitan fatty acid esters (polyoxyethylene sorbitan fatty acid esters), crystalline salts of dodecyl trimethyl protectant bromide (dodecyl trimethyl ammonium bromide), a polyoxyethylene stearate (polyoxyethylene stearate), of aqueous sulfate (sodium lauryl sulfate), sugar fatty acid ester (sucrose fatty acid ester), PEG - cholesterol (PEG-a cholesterol), and combinations thereof selected from vitamin E PEG - (PEG-a vitamin E) is cited.

Said saccharides specific examples, but not limited to, compounds monosaccharide, disaccharide compound, polysaccharide compounds, include substances selected from sugar alcohol and combinations thereof and, more specifically, glucose, lactose, mannitol, shoe crow [cu, xylitol, chitosan, starch from fibrous and combinations thereof chosen is cited.

Part protrudes from the body of the present invention, the nanoparticles of the present invention [...], 1 parts by weight of free base [...], excipient number 0. 01 to 0. 9 parts by weight and, more preferably 0. 01 to 0. 5 parts by weight of excipient include number but, is not limited. The amount of excipient relative to the number of free base [...] final number too if there number is no discomfort increases size is too dose, and dispersibility-term stability of the nanoparticles prepared by the number if the number too is oppositely excipient to door number there could disclosed.

Said [...] nanoparticles a of the present invention, the specification by number to the disclosure method but can be tank, and it is not the limited number bath method.

The present invention according to the method number bath [...] nanoparticles, (1) the free base [...], number and molten excipient solid lipid together behind, the solidified melt; (2) said (1) mixing an aqueous solution number adding excipients obtained in solid mixture, to yield a resultant mixture is dried to form a powder; and (3) said (2) obtained in powder into the pressure rotting, reactor into liquid CO₂ In continuously flowing solid lipid powder industry number comprising the following steps.

Number [...] nanoparticles of the present invention method of said tank (1) step, [...] free base, number and excipient solid lipid together after melting, melt product substrate.

Said (1) step, active title free base (Erlotinib free base) [...] using substrate. The door number [...] hydrochloride (Erlotinib HCl) is intended to provide a solid lipid speed cannot.

Said (1) step, room temperature (for example, 25 provided 30 °C temperature) to keep the solid in solid lipid include, by a relatively low melting point so that said heating 30 provided °C 150 acts as a solvent for the active substance can be easily, hydrocarbon (hydrocarbon) series large lipid solubility in solvent are used. Examples of such solid lipid, 10 - 22 carbon saturated fatty acid, its ester compound and alcohol compound, 10 - 22 carbon atoms having mono or di - saturated region labor pains of fatty compounds, such as 16 or more carbon atoms (e.g., 16 - 24 carbon atoms) hydrocarbon which, triglyceride compounds 10 - 22 carbon atoms also, reduced by the present invention can be used fatty acid product.

Said (1) step, excipients include those described can be used without a prior number number. Part protrudes from the body, (1) a biocompatible polymer in number include excipients, surfactants can be selected from the range of number and combinations thereof.

Said (1) step, 1 parts by weight of free base [...], excipient number is 0. 01 to 0. 9 parts by weight (more preferably 0. 01 to 0. 5 parts by weight) can be used, 1 to 30 parts by weight of solid lipid (more preferably 1 to 20 parts by weight, preferably 1 to 10 parts by weight than) it can be used, not limited. The amount of excipient relative to the number of free base [...] final number too if there number is no discomfort increases size is too dose, and dispersibility-term stability of the nanoparticles prepared by the number if the number too is oppositely excipient to door number there could disclosed. In addition, compared to the amount of free base [...] solid lipid amide is a stand-alone added to the solid lipids number too if there is there may be a door number and diameter number, size of blocks to an opposite solid lipid nanoparticles at l mote [nip too data if thereof can.

Part protrudes from the body of the present invention, said (1) step, [...] free base, number and solid lipid heat from the molten excipient together behind, the melt is cooled roller (e.g., 10 to 25 °C, more preferably 15 to 20 °C roller) preferably in the poured rapidly solidified.

Number [...] nanoparticles of the present invention method of said tank (2) step, (1) adding an aqueous solution mixing number obtained in solid excipient mixture, the resultant mixture is dried to form a powder obtained as follows.

Said (2) step, excipients include those described can be used without a prior number number. Part protrudes from the body, (2) a biocompatible polymer in number include excipients, surfactants number, and a saccharide and combinations thereof can be selected from the range of, excipient number is preferably solid lipid-fluorinated acrylate monomer units can be used.

Part protrudes from the body of the present invention, said (2) step, it comprises [...] solid free base 1 parts by weight, 0. 01 to 0. 9 parts by weight (more preferably 0. 01 to 0. 5 parts by weight) 0 a number of excipients. 5 to 10 parts by weight (more preferably 0. 5 to 5 parts by weight, more preferably 0. 5 to 3 parts by weight) reconstituted with water (e.g., distilled water) or dispersed in a solution followed by addition of solid mixture, kneading machine, mixer, planetary mixer and/or 3 roll mixer to one side after mixing, reduced pressure drying the substrate (for example, in 30 °C hereinafter, more preferably in 25 °C hereinafter).

Number of said bath method of the present invention [...] nanoparticles (3) step, said (2) into the rotting pressure obtained in powder, liquid CO into pressure reactor₂ The powder solid lipids number continuously flowing in a stand-alone substrate.

Part protrudes from the body of the present invention, said (3) step, dried powders prepared by the number 2 in a pressure into the rotting, 10 to 25 °C (preferably 15 to 25 °C), 50 to 130 atmospheres (preferably 65 to 100 atmospheres) under a condition of liquid CO₂ In dried powder flowing continuously into the reactor by a stand-alone number solid lipids, excipient number (a biocompatible polymer, number and/or saccharide surfactants) nanoparticles are dispersed to free base [...] M. substrate.

The pharmaceutical composition of the present invention [...] nanoparticles number using high pressure liquid coolant, the bioavailability of the drug improved, reduced deviation before ingestion of improved convenience meals [...] oral pharmaceutical compositions containing a patient can be achieved.

Thus, according to one aspect of the present invention other, [...] nanoparticles and addition of one or more pharmaceutical composition including a pharmaceutically acceptable number is ball number, which for example, can be used as anticancer number.

1308. elder brother anger number said pharmaceutical compositions to various oral dosage forms. For example, positive number, number ring, contest number have capsules, liquid number, number suspension, emulsion number, number syrup, granules of oral administration of a-number can be any number. For oral administration the number may be effective in addition each number type conventional said depending on the configuration, e.g., peak lactoperoxidase, dextran lactose, sucrose, mannitol, sorbitol, or glycine of cellulosic and/or dilution number, silica, talc, stearic acid and magnesium or calcium salt and/or polyethylene glycol [...] about number of number of number can be include one or more dermatologically acceptable addition.

In addition, when said positive number for oral administration number type, magnesium aluminum silicate, starch paste, gelatin, coating space [su, methylcellulose, sodium vinyl blood raleigh [tin of the car diplopia methyl with the rule which it will count the [cu and/or a like number can be, if necessary, starch, agar, alginic acid or its sodium salt such as a number or disintegrating, boiling mixture and/or absorption number, colored number, flavor or sweetener number further comprises a number such as can be.

In addition, said pharmaceutical compositions or sterile, antiseptic number, stabilizing number, promoting hydration number number or emulsions, such as salts and/or buffer number further comprises auxiliary number for bulking agents may be, other therapeutically useful materials may be further comprises, mixing, granulation or coating conventional method of number number according can be disclosed.

Active ingredient, i.e., the free base [...], for mammal including human, day 0. 1 to 500 mg/kg (body weight), preferably 0. 5 to 100 mg/kg (body weight) in a therapeutically effective dose of said pharmaceutical compositions can be included, such pharmaceutical composition orally administered agent 1 1 can be divided into 2 or more times.

Said pharmaceutical compositions, preferably enteric number number (capsule or positive number) implementation being.

Said pharmaceutical compositions, preferably drug free base of 2 times before implementation being hereinafter [...] fore-aft test meals bioavailability deviation.

Said pharmaceutical compositions, preferably in less than 5 come into equilibrium concentration in fasting intestinal (FaSSIF provided v2) 60% or more can be reached.

[...] using number number of free base of nanoparticles in simulated intestinal (FaSSIF provided v2; fasted state simulated intestinal fluid version 2, FeSSIF provided v2; fed state simulated intestinal fluid version 2) eluting pattern is, commercially available number number (Tarceva^® Tablet) via equilibrium concentration was achieved (in the embodiment 4) in which the release of very quickly. Elution rate is aligned or not the bioavailability is increased, in particular of drug elution rate of post-prandial intestinal (FaSSIF provided v2) before the bioavailability increased bioavailability levels in post-prandial aligned or not is deviation of can be reduced disclosed (The Open Drug Delivery Journal, 2010, 4, 2 - 13).

Computer readable signals [...] number 1 solution (pH 1. 2) nanoparticles of very rapid dissolution rate in the rust but all lie within minutes and 5 free base [...], the solutions are transferred [...] autobody number 2 solution (pH 6. 8) when the dilution is sized particles of precipitation it becomes, abruptly precipitation unit to micro, nano particles number using number number number number number number on the fore-aft (beagle dogs) commercially available nanoparticles under normal capsule drug testing high pressure liquid coolant is similar bioavailability pattern and viscoelasticity (in the embodiment 6).

While the present invention is sold at 30 min or higher (in the embodiment 4) experiments and simulated intestinal using even number number but prevents air from reaching the equilibrium concentration, using number may be [...] free base of nanoparticles 20 minutes, preferably 15 minutes, more preferably about 5 minutes 10 micro g/ml was achieved equilibrium concentrations.

In addition experimental dilution (in the embodiment 5) displaying after dispersed even at a high concentration, dilution concentration of 60% or more (for example, 60 - 99%) equilibrium in every 5 minutes, preferably 70% or more, more preferably 80% or more of the elution rate fast reaching bix, his car constant amount in addition to be eluted in 5 minutes. However in the case of a kind that the slower elution rate the displayed number number Tarceva in commercially available is also used for the dilution were.

Pharmaceutical compositions of the present invention enteric capsule number beagle dogs may be relatively drug bioavailability of the part is before the fore-aft test, commercially available 5 - 7 times before meals was 2 times hereinafter show variation in bioavailability number number (e.g., 1. 1 - 2 times) (glucose levels: 14,372 (ng/ml)* h, before: 7,972 (ng/ml)* h) to improve the working. Intestinal drug absorbed drug can be increased power output from the power to remain on the time, generally 60 to 110 minutes in time when drug passes a small intestine of prandial, lessening post-prandial 150 to 180 min. (Sutton, S. C. , 2004. Companion animal physiology and dosage form performance. Adv. Drug Deliv. Rev. 56, 1383 - 1398.) to time 2 times before contrast levels passes a small intestine but further required, in the case of condition or state 3 to 4 passes a human small intestine-prandial levels both same time time (Davis, S. S. , Hardy, J. G. , Fara, J. W. , 1986. Transit of pharmaceutical dosage forms through the smallintestine. Gut 27, 886 - 892.) up. The, about 5 to 7 times the fore-aft beagle dogs at each relatively drug bioavailability in the thread number number number about 1 commercially available human visible deviation before meals. 6 times before meals bioavailability deviation not outside it are disclosed. If this fact field pockets, relatively drug fore-aft beagle dogs at each about 1. 8 times the number may be enteric capsule of the present invention pharmaceutical compositions bioavailability was visible deviation before meals, chamber number 2 times hereinafter human may be permitted before meals bioavailability deviation (for example, 1. 1 - 2 times, or 1. 1 - 1. 5 times) either, more preferably produce little or no the diagram (for example, 1. 0 - 1. 1 times) are expected. I.e., a herb medicine in post-prandial, even almost equivalent to the amount absorbed dose blood meals taken without the severe state according to slight differences are disclosed.

Current commercially available relatively drug fore-aft of human number number according experiments, with 100% oral bioavailability is administered to allow fat type telephone, the 60% post-prandial oral administration are disclosed. Thus, according to the control signals according to the individual dose to reduce the side effects of excessive food absorption, times 1 time 1 1 before pre, post-prandial take over 2 hours to the diabetics. The pharmaceutical compositions of the present invention commercially available on which the number number lower than the dose equivalent effect, in addition to food stored in the administration of drug infusion influences the risk structure to increase efficiency can be therapeutic ribs ingestion of patient.

Hereinafter, the present invention through more detailed but in the embodiment, the present invention is to explain the hell of, in the embodiment of the present invention what type way number one by range are not disclosed.

[In the embodiment]

In the embodiment 1

Active ingredient [...] free base (Erlotinib free base, 20g), solid lipid as an steel alcohol (myristyl alcohol as solid lipid, 100g), polyvinyl pyrrolidone as excipients in a number 130 °C (polyvinylpyrrolidone k17 as excipient, 6g) is produced by co (co non-melted), by rapidly solidifying in 15 °C (solidifying), solid mixture was uniformly dispersed in alcohol at l mote [nip number pre-steel high pressure liquid coolant. The solid mixture (Hydroxypropylcellulose (ssl): Distilled water=6g: 40g) HPC-a ssl (Hydroxypropylcellulose provided ssl) aqueous solution after adding and mixing, reduced pressure drying up. The dried solid dispersion (solid dispersion) is placed a pressure reactor (Bio-a synectics, BS provided SF1, South Korea), 60 to 100 atmospheres, 15 to 25 °C under a condition of continuously flowing liquid carbon dioxide into the reactor and the number present at l mote [nip with a stand-alone number only in solid dispersion solid lipid excipients NufsERT powder 30. 5g (yield: 95. 3%) number was a high pressure liquid coolant.

NufsERT powder prepared by the number, 0 [...] reference. 5 mg/mL distilled water to be dispersed and (distilled water), high pressure liquid coolant in the steam after 30 minutes agitating dispersion number 37 °C, ELSZ provided 1000 (Otsuka Electronics Co. , Ltd, Osaka, Japan) using particle size were measured. Particle size the result of measurement as follows.

In the embodiment 2

In NufsERT prepared by the number 4 °C powder in the embodiment 1, 2 in 25 °C and 40 °C while storage for one month or more, according to particle size change time observed. Observations as follows.

40 °C, 4 °C, about two months NufsERT powder dispersed in low temperature to ambient temperature between from the cell compartment, within which the initial particle size about 20% the size change, making sure that the capable of maintaining initial particle size. (NufsERT initial dispersion particle size: 250. 2 nm)

In the embodiment 3

High pressure liquid coolant in a number NufsERT powder in the embodiment 1, D - mannitol (D-a mannitol) and mixtures of aluminum oxide and twin 80 (TW80) evenly mixed at a ratio of glycolic acid starch sodium (Sodium Starch Glycolate) number table below was produced which powder filling high pressure liquid coolant. Common gelatin or enteric gelatin capsule filling mixed powder 316 ± 2mg-gate.

In the embodiment 4

Intestinal (FaSSIF provided v2; fasted state simulated intestinal fluid version 2) or before meals to 500 ml simulated intestinal (FeSSIF provided v2; fed state simulated intestinal fluid version 2), high pressure liquid coolant in the embodiment 3 number NufsERT Tarceva commercially available powder in capsule filling^® Pulverizing powder tablet, adding amount are arranged corresponding to each reference 10 mg free base [...] test of abortion. 37 ± 0 eluate during the experiment. To 5 °C, 75 rpm paddle speed was maintained. 1, 3, 5, 7, 9, 11, 30, 120 and 3 ml component sampling (sampling), new intestinal 3 ml with sweets. Sampling the inside Agela PTFE filter (0 NufsERT powder is dispersed in the case of the present invention. 22 micro m filter, Tarceva^® Powder is dispersed in the case of the present invention 0. 45 micro m filter) is filtered has surpassed its initial 2 ml, HPLC analysis by remaining filtrate was analyze the amount eluted.

In the embodiment 5

37 ± 0. 5 °C by a user before a simulated intestinal (FaSSIF provided v2; fasted state simulated intestinal fluid version 2) or intestinal glucose levels to 50 ml (FeSSIF provided v2; fed state simulated intestinal fluid version 2), high pressure liquid coolant in the embodiment 3 number NufsERT Tarceva commercially available powder in capsule filling^® Pulverizing powder tablet, adding amount corresponding to each reference 10 mg free base [...], 75 rpm paddle speed to and mixing elution test of abortion. Adding a sample to sample after 20 minutes to allow stirring, 3 ml sampling, new intestinal (fresh FaSSIF provided v2 media or FeSSIF provided v2 media; hereinafter dilution eluate) 53 ml through the 1/2 dilution to dissolution by the enemy. 5 minutes 3 ml again been rapidly sampling, 103 ml eluate into dilution and, after 5 minutes stirring 3 ml again sampling, dilution is performed 203 ml eluate elution test apparatus with the manner, dilution according to elution rate were measured. Sampling the present invention, the filtration of the same method as in the embodiment 4 after HPLC analysis are arranged amount were measured. A result of the determination as follows.

Results from dilution by an eluate eluted on newly added amount by computing table below such as disclosed.

Capsule for powder dissolved in a uniform speed but added dilution NufsERT eluate, Tarceva^® In the case of dilution chart powder dissolution rate increase is know before arcing occurs on the first call.

I.e. the present invention according to NufsERT powder dissolved Tarceva speed per unit time^® Fast powder removing cells were compared.

In the embodiment 6

Beagle silk (Beagle dogs, 9. 3 - 10. 7 kg) 12 3 4 mary mary randomly by group (Tarceva^® , General NufsERT and an enteric capsule) has been divided into. 23 ± 3 °C test temperature, 55 ± 15% relative humidity, ventilation times 10 - 20 times/hr, 150 - 300 Lux and illumination time (morning ∼ afternoon when the turn signal lamps 8 8 off) 12 lighting time set environment been embodiment. That the dinner meal time Canine Feed (Cargill Agri Purina Inc. , Korea) 300g taken by a free part directly, water is optionally the main intake.

Before dynamics and 16 hours before experiments experiments to a nanoparticulate (water is number ball), 100 mg Tarceva commercially available^® In the embodiment 3 30 ml with water in a high pressure liquid coolant or a number NufsERT capsule (100 mg reference Erlotinib free base) was administered orally. 2 proceeds after wash a-out period of daytime levels dynamics experiments, drug administration 20 minutes before 200g solid type (NATURISTM Infant & Puppy containing 13% fat, ACI Group Ltd. , UK) supply, 100 mg Tarceva commercially available^® In the embodiment 3 30 ml with water in a high pressure liquid coolant or a number NufsERT capsule (100 mg reference Erlotinib free base) was administered orally.

Tarceva^® General capsule administration group NufsERT before drug administration group (0), 0 after administration. 25, 0. 5, 0. 75, 1, 1. 5, 2, 3, 4, 6, 8, 12, 24, 48 and time, NufsERT enteric capsule before drug administration (0), 1, 1 after administration. 5, 2, 2. 5, 3, 3. 5, 4, 5, 7, 10, 12, 24, 48 and jugular vein after blood collection through time heparin processing (5 IU/ml) of the blood in the storage [...] tube 5 minutes (Eppendorf tube) centrifuging the blood plasma via a 3000 rpm are separated from each other, when the archiving -70 °C to him.

LC (liquid chromatography) separated depletion method of API ion source at l mote [nip consistency (Atmospheric Pressure Ionization) Mass Spectrometer (AB Sciex, Framingham, MA, USA) equipped with a sensing element to him. Analysis results shown under the table.

Tarceva^® In the case of general capsule and NufsERT, AUC glucose levels before each about 5. 8 times, 5. 3 times differ activated, C_Max 5 each. 3 times, 4. 5 differ times out. However in the case of enteric capsule NufsERT, AUC is 1 before meals. 8 times, C_Max The 1. 1 Tarceva times^® (NufsERT and general capsule) before contrast levels to drastically improved in bioavailability deviation and viscoelasticity.

The organic [...] (free base) number and a high pressure liquid coolant, in the form of oral bioavailability to enteric (capsule or positive number) administered to allow excess capacity can be solved by first and second pharmaceutically active oral administration as well as reduce side effects, surprisingly improved bioavailability deviation before meals can increase the efficiency of a treatment by a chucked by ingestion of a patient are disclosed.