JP2003522097A - Solubilized delivery system and manufacturing method - Google Patents

Abstract

  (57) [Summary] By mixing the active / surfactant combinations using the selected processing conditions, the eutectic of the combination is brought into intimate contact with the particles of the active ingredient, at least in part. This mixing process makes it possible to increase the solubility of the active ingredient and to increase the concentration of the active ingredient to be dissolved, which was previously possible.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION

The present invention relates to a solubilized delivery system for easily dissolving a hardly soluble substance therein in an aqueous solution, and a method for producing the same. In particular, the solubilization system is a combination of active substance / solubilizing agent eutectic composition in intimate contact with particles of active substance. When the active agent is a pharmaceutical material or drug, this solubilized delivery system product is then prepared by preparing a edible unit such as a tablet or capsule or an oral dosage form, followed by a suitable amount of conventional pharmaceutical ingredients. Mixed with.

[0002]

【background】

The manufacture of drug / polymer mixtures that combine drugs with polymer melts is known. Their manufacture includes the concepts of melt mixing and extrusion. Drugs have been mixed with molten surfactants or dispersions of surfactants to produce solid solutions of the drug in the surfactant. PCT application WO 97/02017, published January 23, 1997, shows the use of pluronic surfactants as dissolution aids for various drugs, including ibuprofen, in sustained release formulations. In the melt mixing operation disclosed therein, the drug was added to the surfactant at a temperature above the melting point of the surfactant. In the 1994 and 1997 literature, BASF Corporation discloses melt extruded drug / polymer products, but no specific preparations thereof.

In an abstract entitled "Application of Crosslinking Agents to Ibuprofen / Xylitol Solid Dispersion Systems", Greenhalgh et al. Use pluronic surfactants to overcome the immiscibility of ibuprofen in xylitol. Is disclosed. They teach and disclose a mixture of ibuprofen and Pluronic F68 as forming a eutectic mixture having a melting point of 38 ° C. Drug Development and Industrial Pharmacy, Vol.23, No.6, 1997, pp561-56
According to the abstract in a paper entitled "Compatibility of Ibuprofen and Ethenzamide" in 5, the chemical stability of ibuprofen with various drugs was investigated.
The researchers reported that a eutectic mixture was formed between ibuprofen and ethendamide. In addition, they reported that the chemical stability of the eutectic mixture in capsule form (with a small amount of excipients) was found to be stable. These investigators also reported that a "significant" delay in dissolution was observed when this covalent was formed at temperatures above 56 ° C (the melting point of the eutectic mixture).

However, these disclosures do not recognize or teach the reason for dissolution delay in drug / polymer (dissolvent) eutectic mixtures processed at temperatures above the formation temperature of the eutectic mixture. Moreover, they found that despite such drug / polymer (solubilizer) eutectic mixtures improving the solubility of the drug, the "load" capacity of the solubilizer was low, ie Again, it does not teach that a finished, salable drug product cannot be produced because only a relatively small amount of active ingredient can be "loaded" before the opposite solubility characteristics come into play. The low "loading" of such active ingredients means that
An oversized dosage form will be provided so that a sufficient quantity of the active ingredient can be delivered to the patient. Thus, there is a need for a high "load" delivery system that takes advantage of the high solubilizing properties of the combination of solubilizer and surfactant.

[0005]

[Outline of the Invention]

The present invention provides that the particles of at least one active agent and at least one solubilizing agent, such as a surface active agent, are at low temperature (ie below the melting point of both), preferably a combination of active agent and solubilizing agent. The solubilized delivery system and the process for producing the same, wherein the solubilized delivery system is processed at a temperature from below the eutectic mixture formation temperature to below the temperature at which the active substance dissolves in the solubilizer. The processing is further carried out in the presence of sufficient force at the processing temperatures mentioned above to produce an active substance / solubilizer eutectic mixture which at least partially coats or is in intimate contact with the active substance particles. , And mixing these ingredients. Preferably, the particles are the crystalline form of the active ingredient, which is at least partially surrounded or encapsulated by the eutectic mixture of active ingredient and solubilizer. The eutectic mixture may also contain crystals of the active ingredient. For active ingredients intended to be absorbed in the intestine, such as ibuprofen, the solubilizer / active ingredient system produced according to the invention exhibits superior water solubility at pH 5.2 compared to the active ingredient alone. %, Preferably from about 30% to about 90%, most preferably from about 40% to about 80%.

Applicants have found that certain active ingredients (especially drugs) are present in the solubilizer under sufficient force (eg shear, centrifugal force or pressure) below the formation temperature of the eutectic mixture. It has been found that it will form a eutectic mixture with certain solubilizers when processed at temperatures below the temperature at which it melts or melts. These eutectic mixtures will at least partially coat or encase the particles of active ingredient (solubilized delivery system) in the presence of the above temperatures and forces. This solubilized delivery system contains a higher proportion of active ingredient than does the eutectic mixture alone, while maintaining the increased solubility properties of the eutectic mixture or coalesced product of solubilizer and active agent. it can. The resulting product is then further processed (eg milled) to form microparticles which are further processed into drug dosage forms.

In a preferred embodiment, the drug / solubilizer solubilizing delivery system comprises, at least in part, particles of drug coated with a drug / solubilizer eutectic mixture. This product, when ingested, produces a plasma profile that indicates that the drug is available for ingestion by the body much more rapidly than is available.
In addition, this product can carry larger amounts of drug than the eutectic mixture alone. Upon dissolution of the solubilized delivery system, the rapidly dissolving eutectic mixture is believed to provide the initial amount of active ingredient followed by the drug in particulate or crystalline form moistened with the solubilizer.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to granules (eg crystals) coated with a eutectic mixture of an active ingredient and a solubilizer, combining the respective ingredients under controlled temperature and processing conditions. To a particulate active ingredient / solubilizer product by obtaining particles of the active ingredient as well as a product containing particulate solid active ingredient coated with the eutectic mixture. A eutectic mixture is a combination of substances whose melting point is lower than any other combination of the same components. Typically, the eutectic mixture melts below the melting point of the individual components. As used herein, an active ingredient or substance means any substance or material for which it is desired to improve its solubility or solubility properties. The drug substance is the most preferred active ingredient. Such materials and ingredients will be readily apparent to those of ordinary skill in the art reading the present invention.

In a preferred embodiment, the drug / solubilizer solubilization delivery system of the invention has a dissolution profile such that about 80% or more of the drug dissolves in water at pH 5.2 within about 5 minutes at 37 ° C. Will have. However, when the mixture of ingredients is heated to a temperature well above the eutectic alloy formation point, the crystals of active ingredient dissolve or melt in the solubilizer to give a saturated or saturable solution. Upon cooling of the dissolved or molten active ingredient, it recrystallizes into crystals which are too large to benefit the improved wetting of the solubilizer / eutectic mixture coating and are not readily dissolved.

The method generally comprises about 10% to about 95%, more preferably about 30% to about 90%, most preferably about 40% to about 80% of at least one active agent, about 90% to about 90%. 5%, more preferably from about 10% to about 70%, most preferably from about 20% to about 60% of at least one solubilizer, with the drug from below the eutectic mixture formation temperature of the drug / solubilizer mixture. The processed drug / solubilizer product is mixed by mixing in the presence of sufficient force to at least partially coat particles of the active ingredient at a temperature below the temperature at which it melts or dissolves in the solubilizer. Including collecting. Optionally, the particle size of the recovered product can be further reduced, for example according to known grinding processes. When utilizing milling or other particle size reduction methods, care must be taken that the temperature does not significantly exceed the original processing temperature or else large particles will form again in the eutectic mixture.

<Components> A. Active substance: The active substance is generally a poorly soluble solid substance, preferably an intrinsic crystal. Also, the size of the particulate or crystalline solid material is small, preferably less than about 10 microns, and most preferably about 6 microns or less. Preferably, the active agent is a drug whose rapid dissolution and release is desired, but whose dissolution profile inhibits rapid dissolution. Among them, useful drugs are analgesics, H2 antagonists, nonsteroidal anti-inflammatory agents, anticholesterolemia agents, antiallergic agents and antimigraine agents. Ibuprofen (IBP), ketoprofen, and naproxen are especially preferred drugs.

[0012] Other useful drugs include dextromethorphan, chlorpheniramine maleate, 4-acetamidophenol (APAP), sodium naproxen, diphenhydramine, diltiazem HCl, cimetidine, and fexofenadine (Fexofenadine). ) Is included. Any active agent or drug that forms a eutectic mixture with the solubilizer can be used and is considered to be included in the present invention. While the operation of processing equipment can result in some wear, it is generally desirable to provide the drug in finely divided form to facilitate the formation and coating of the eutectic mixture. Ideally, the particle size of the drug before processing should be less than about 10μ, preferably less than 6μ.

B. Solubilizers: The solubilizers used can generally have both hydrophilic and hydrophobic (HLB) characteristics. However, an important feature of the solubilizer is its ability to form a molten mixture with the material with which it is to be processed. Generally, the melting point of the solubilizer or combination of solubilizers should be lower than that of the active ingredient. In addition, between the melting point of the solubilizer and the melting point of the active ingredient there is sufficient "overhead space (so that the combination can be processed at a temperature low enough that the active ingredient does not dissolve in the solubilizer. head room) ''
Is preferably present. If an excess of the active ingredient is dissolved in the eutectic mixture, the active ingredient will form crystals on cooling, and if this increases, it will not be possible to take advantage of the wetting effect of the solubilizer, and thus easily Will not dissolve.

For some drugs, poloxamer surfactants are particularly useful. Polyoxyethylene / polyoxypropylene surfactants such as Pluronics / Lutrols manufactured by BASF Corporation are particularly effective. Pluronic or Lutrol F68 are particularly preferred. Other useful surfactants include PEG-1000 and PEG-2000 and the like. Solubilizers useful for other drugs can be salts or other pharmaceutically acceptable compounds that form a eutectic mixture and melt at a lower temperature than the drug to be mixed.
Among these is urea. About 90% to about 5%, more preferably about 10% to about 70%, most preferably about 20% to about 6.
It is preferred to utilize 0% solid solubilizer in the solubilizer delivery system of the present invention. In any case, sufficient coverage or encapsulation of the particles of active ingredient,
Sufficient solubilizer must be present to enhance their solubility.

C. Method: The method of the invention comprises contacting solid particles of the active ingredient, including the drug, with a solubilizer under conditions suitable to form the delivery system product of the invention.
Following manufacture of the product, the particulate product is generally screened and used in dosage forms with other pharmaceutical additives. Preferably, the temperature at which these ingredients are contacted is below the formation temperature of the eutectic mixture of the combination to below the temperature at which the active ingredient dissolves in the solubilizer so that not all of the drug is dissolved in the eutectic mixture. Is the temperature. If the temperature is too high, one or both components will crystallize rapidly upon cooling, resulting in crystal reformation that is too large to benefit the wetting properties of the solubilizer / eutectic mixture.

Typical temperatures used in the present invention are from below the standard eutectic mixture formation temperature to below the temperature at which the active ingredient melts or readily dissolves in the solubilizer used.
X-ray diffraction has revealed that upon cooling, crystals of the active ingredient and the solubilizer are formed in the eutectic mixture. However, these crystals are very small unless the active ingredient dissolves or is present in too high a concentration. In addition, a combination of temperature and force (particularly shear) is used to form a eutectic mixture at temperatures below the "normal" eutectic mixture formation temperature under normal atmospheric pressure to coat particles of the active ingredient. It is possible. For coating, it is also important that the processing temperature is sufficiently high in order to control the viscosity of the mixture and allow the particles of active ingredient to be coated by said force. For the combination of ibuprofen and Lutrol (Pluronic) F68, the preferred temperature is about 35 to about 45 ° C.

When the temperature must be kept low to prevent dissolution of the active substance,
Increased viscosities may be encountered, which makes coating difficult, with increased processing forces or increased residence time of the material in the presence of these forces. Forces used during processing include, but are not limited to, centrifugal force, shearing force and pressure.
Shear and centrifugal forces are preferred. However, no matter what force the material receives,
This force must be sufficient to coat the eutectic mixture on the active ingredient crystals or particles. Generally, the higher or higher the force applied for a longer time, the more complete the coating. In addition, a sufficient amount of each component must be used to fully coat or envelop the particles of active ingredient, or the enhanced solubility properties will not be fully realized.

D. Equipment: The method of the present invention is carried out on any equipment that provides conditions of temperature and force to promote formation and optionally coating / encapsulation of the eutectic mixture. Suitable equipment includes extruders, flash flow spinning heads.
ead) etc. are included. One highly preferred apparatus is a multiple zone extruder having a sufficient length / line ratio (L / D) to coat or encapsulate the active ingredient with a eutectic mixture of active ingredient / solubilizer. ). In addition, flash flow spinning heads are useful. Inside the device, the source particles lose their resistance to liquid flow and become “liquid”. In this state, the eutectic mixture physically deforms from its original solid state through the liquid state and immediately returns to the solid state. During this deformation, the particles are subjected to centrifugal or other shear forces that separate them into individual eutectic-coated particles. US Patent No. Issue describes the details of this liquid flush stream process.

The solubilized delivery system particles are then milled by known methods, such as milling, and optionally sieved to separate the particles of sufficient size for the dosage form containing them. . This size reduction method should be monitored to prevent the delivery system particles from reaching temperatures above those used in their manufacture, otherwise large crystal formation will occur. . Once sized, these particles may be mixed with suitable amounts of various pharmaceutical ingredients such as sweeteners, fillers, flavors, flow control agents and binders and the like. Such dosage forms can include tablets, capsules and other oral dosage forms.

E. Combination: The active ingredient and solubilizer are about 95: 5 to 10:90, preferably about 90:10 to about 25: 7.
5, most preferably about 80:20 to about 40:60 active ingredient: solubilizer ratios should be combined, the appropriate ratio being determined by the characteristics of these ingredients. In general, it is preferred that the active ingredient be present in the highest possible amount without compromising the improved solubility of the present invention. When IBP and the surfactant Lutrol (Pluronic) F68 are used in the process of the present invention, the particles of IBP are coated (at least partially, preferably completely) with a eutectic mixture of IBP and Lutrol F68. It Eighty percent of the solubilized delivery system thus produced will dissolve in water at pH 5.2 at 37 ° C in 5 minutes as measured by the Beckman / Hanson automated dissolution system described below. The preferred ratio of IBP to Lutrol F68 is about 60:40 to about 75:25.

It is believed that the additional combination of an additional drug such as ketoprofen or naproxen with a solubilizing agent such as Lutrol F68, which forms a eutectic mixture therewith, would be particularly useful. In particular, active ingredients such as drugs have been discussed above and are also exemplified below. However, the invention includes any combination of ingredients in which improved solubility or solubility of one ingredient (active ingredient) is useful. As indicated, the active ingredient must form a eutectic mixture with a solubilizer or combination of solubilizers that can be coated onto particles of the ingredient. Such materials and ingredients will be readily apparent to those of ordinary skill in the art upon reading this invention.

[0022]

【Example】

The following examples illustrate the process of the present invention and the preparation of the novel products by way of example only and are not intended to limit the scope of the present invention. Example I Poloxamer 188NF (Lutorol F68) was ground by passing it through an Apex 114 mill using a 20 screen equipped with a hammer. The feed rate was 4 PRM and the mill speed was 4590 RPM. The mill was cooled for 15 minutes and then the material was run with the same settings. 9.76 kg of micronized ibuprofen (IBP) and 6.60 kg of ground Lutrol F68 were added to a Dosna V100 mixer in the following order: (1) 1/2 of solubilizer, (
2) All IBP, (3) Remaining solubilizer. The ingredients were mixed with the chopper off and at speed II for about 5 minutes to produce a 60:40 IBP: Lutrol mixture. This mixture was used as the feedstock as follows. The feedstock was fed to the spinning head disclosed in US patent application Ser. No. 08 / 874,215 filed June 13, 1997. The head speed was increased to 60 Hz while raising the heating element to a temperature that produced a liquiflash condition. The material was passed through the orifice of the spinning head and the product was allowed to fall 6-8 feet below the head. The product consists of particles coated with a eutectic mixture containing IBP: solubilizer = 60: 40.

Example II The same mixture of IBP / Lutrol F68 as in Example I was made as described in Example I. However, instead of passing the mixture through the prevention head, the AV
The extruder manufactured by P was used. Set the APV extruder with a water bath set at 20 ° C, turn on the heater and stabilize at 40 ° C. The hopper is filled with the IBP: Lutrol mixture and the exit orifice is heated with a heat gun until molten material is present. Start extruder at 50 RPM until product is seen exiting the exit nozzle (~ 1 min). Feed the mixture continuously until all temperatures have stabilized, then
Set RPM to 250. The process is allowed to proceed continuously for 5 minutes, then the product is collected on a plastic lined tray. Additional runs were performed using different RPM speeds and L / D (25 and 15) and with or without the exit nozzle in the correct position. These runs are products with particles of IBP apparently completely coated with the eutectic mixture, or high L / D, slow RPM.
Alternatively, the eutectic mixture produced a product that was not intimately attached to the crystals of IBP, using the nozzle in the correct location. The dissolution test results shown in Graph 1 also support the requirement of sufficient force and low temperature.

Example III: Extrusion Milling The extrudate is passed through an Apex 114 mill without mesh and hammer. 4 RPM
Feed the mixture very slowly, with a feed rate of 4590 and a mill speed of 4590 RPM. Care should be taken that this milling process does not generate excess heat. Collect the milled material and pass it through the mill again using a No. 6 screen and the same settings. Before continuing the feed, feed the hopper again very late to avoid excess heat and empty the top of the feeder.

Example IV: Ibuprofen Dissolution Test Extruded and Liquid Flash Formed and Milled Particulate IBP of Examples I-III
: Lutrol materials were tested for solubility according to the following method. Some results are shown in Chart 1 below. Equipment: USP 711 equipment 2 (paddle) operated under the following conditions: Speed: 50 RPM Temperature: 37.0 ± 0.5 ° C Medium: pH5.2 phosphate buffer, 900 mL Sampling time: 5, 10, and 20 minutes UV spectrophotometer Wavelength: 266 nm Cell path length: 1.0 cm

Procedure: 1. Dispense 900 ml of medium into each dissolution vessel. 2. Degas the medium by purging with nitrogen for 3 minutes. 3. Set up the lyser (Beckman / Hanson automated lysing system) by checking the paddle height and equipping the sample probe with a 10 micron prefilter. Equilibrate the medium to 37.0 ± 0.5 ° C. 4. Weigh sufficient sample to contain 200 mg of IBP. Place the sample in each container. Lower device to appropriate level. Start the device with the parameters specified above. 5. At specific times, the automated device draws a sample from each container and analyzes by UV spectrophotometer.

[0027]

[Table 1]

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, C H, CN, CU, CZ, DE, DK, EE, ES, FI , GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, L K, LR, LS, LT, LU, LV, MD, MG, MK , MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, T M, TR, TT, UA, UG, UZ, VN, YU, ZW F-term (reference) 4C076 AA31 AA36 AA44 AA53 BB01                       CC01 CC03 CC05 CC11 CC14                       DD09E FF15 GG17                 4C206 AA01 AA02 DA22 DA24 DA25                       KA01 KA04 MA02 MA05 MA55                       MA57 MA61 MA72 NA02 NA13                       ZA02 ZA08 ZB11 ZB13 ZC33                       ZC44

Claims (14)

[Claims] 1. A method of making an active ingredient / surfactant solubilized delivery system product comprising: (a) about 10 to about 95 parts of at least one particulate active agent; and about 90 to about 5 parts. Mixing with at least one solid solubilizer; (b) at a temperature below the eutectic mixture formation temperature of the active agent and the solubilizer to below the temperature at which the active agent dissolves in the solubilizer. Producing a eutectic mixture of active agent and solubilizer and processing under conditions of sufficient force and residence time for the eutectic mixture to at least partially intimately contact the active agent particles; and (c) ) Recovering the manufactured active ingredient / surfactant product. 2. The method of claim 1, further comprising milling or otherwise grinding the active ingredient / surfactant product into particles of a desired size. 3. The method of claim 1, wherein the particulate active agent and solubilizer are in a ratio of about 30 parts to about 90 parts active agent and about 70 parts to about 10 parts solubilizer. How to be mixed. 4. The method of claim 1, wherein the particulate active agent and solubilizing agent are in a ratio of about 40 parts to about 80 parts active agent and about 60 parts to about 20 parts solubilizing agent. How to be mixed. 5. The method according to claim 1, wherein the active substance comprises an analgesic agent, an H2 antagonist, a nonsteroidal anti-inflammatory agent, an anticholesterolemia agent, an antiallergic agent and an antimigraine agent. The method being a drug selected from. 6. The method of claim 5, wherein the drug is selected from the group consisting of analgesics. 7. The method of claim 6, wherein the analgesic agent is selected from the group consisting of ibuprofan, ketoprofen and naproxen. 8. The method of claim 1, wherein the active agent is ibuprofen (IBP) and the ratio of IBP to solubilizer is about 60:40 to about 75:25. 9. A solubilized delivery system comprising at least one particle of active agent and at least one solubilizing agent in a ratio of about 10:90 to about 95: 5.
The at least one active agent and the at least one solubilizer form a molten mixture,
A solubilized delivery system in which the molten mixture is at least partially in intimate contact with the particles of active agent. 10. The delivery system of claim 9, wherein the particles of active ingredient and the solubilizer are about 40 parts to about 80 parts active material and about 60 parts to about 20 parts solubilization. A delivery system that mixes in the ratio of agents. 11. The delivery system according to claim 9, wherein the active substance is an analgesic agent, an H2 antagonist, a nonsteroidal anti-inflammatory agent, an anticholesterolemia agent, an antiallergic agent and an antimigraine agent. A delivery system that is a drug selected from the group consisting of: 12. The delivery system according to claim 11, wherein the drug is selected from the group consisting of analgesics. 13. The delivery system according to claim 12, wherein the analgesic is selected from the group consisting of ibuprofan, ketoprofen and naproxen. 14. The delivery system according to claim 13, wherein the active substance is ibuprofen (IBP), and the ratio of IBP to the solubilizer is about 60:40.
A delivery system that is about 75:25.