Preparation of drug particles using evaporation precipitation into aqueous solutions

a technology of evaporative precipitation and drug particles, which is applied in the field of drug particles, can solve the problems of poor bioavailability, difficult to produce highly uniform submicron particles, and wet milling techniques exhibit problems, and achieve high drug activity, high dissolution rate, and high potency

Inactive Publication Date: 2014-01-30
BOARD OF RGT THE UNIV OF TEXAS SYST
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a method of making small drug particles using a process called evaporative precipitation into an aqueous solution. These particles have the advantage of being highly soluble in water, which makes them easier to absorb by the body. The method also allows for better control over the particle size and shape, and can produce particles with reduced crystallinity, which further enhances their dissolution in water. Overall, this method can improve the bioavailability of poorly soluble drugs and make them easier to use in medications.

Problems solved by technology

Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water.
However, such wet milling techniques exhibit problems associated with contamination from the grinding media.
It is difficult to produce highly uniform submicron particles with wet milling and solids milling, and handling can be time consuming.
Moreover, exposing a drug substance to mechanical shear or high temperatures for prolonged periods can cause the drug to lose its activity.
Spray drying is used commonly to formulate dry pharmaceutical powder, in most cases, either hydrophilic drugs in aqueous solution or poorly water soluble drugs in organic solution are sprayed, which approaches do not offer a means to simultaneously spray a poorly water soluble drug and water soluble excipient.
It is difficult to produce sub-micron particles by these technique due to growth of the drug particles during the solvent evaporation.
Moreover, in all of these teachings, the precipitation of surfactant, or other excipient, and stabilizers occur simultaneously in the coaxial nozzle, and it is much more difficult to control the particle morphology.
Furthermore, in all of these teachings, the useful excipients are sugars, salts, pectin and citric acid, which are not good stabilizers for preventing growth of particles during the spray process.
In most cases this process does not utilize water due to the low solubility of water in compressed carbon dioxide, so that it is difficult to use water-soluble excipients with this process.
In this process it is difficult to control the particle size due to the complexity of the mixing of the three streams in the jet.
Moreover, as the water contacts CO2, the pH in the water reaches 3, which can be detrimental to drug stability and interactions with excipients.
The solubility of drugs in carbon dioxide and other supercritical fluids such as ethane and propane is typically very small.
It is difficult to add water soluble stabilizers and excipients in spray antisolvent processes (PCA, SAS or SEDS) into carbon dioxide due to the low solubility of water in CO2.
Even when an aqueous and two organic solutions are sprayed through a coaxial nozzle, the process is subject to many of the limitations discussed above for spray drying organic and aqueous phases through coaxial nozzles.
As the water dissolves into the ethanol-carbon dioxide mixture, it is no longer available to solvate stabilizers to prevent particle growth.
Therefore this process is limited to relatively few drugs.
An additional challenge for poorly water soluble drugs is to achieve high dissolution rates with a high drug-to-excipient ratio or high payload.

Method used

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  • Preparation of drug particles using evaporation precipitation into aqueous solutions
  • Preparation of drug particles using evaporation precipitation into aqueous solutions
  • Preparation of drug particles using evaporation precipitation into aqueous solutions

Examples

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examples

[0067]For the following examples, the apparatus shown in FIG. 1 is used. The drug / organic mixture was fed via a Constametric 3200 HPLC pump through a preheating coil into a 30 mL receiving tank containing the required amount of aqueous solution. The nozzle used for the spraying was made by cutting 1 / 16″ stainless steel tubing to form an elliptical conical geometry at the end. The end of the tube was filed to obtain the desired flow rate. Nitrogen was continuously flowed downward to break up foam in cases where it formed. For all of the examples, particle size was measured by dynamic light scattering techniques within 4 hours of the spray.

[0068]Dissolution testing for the following examples was carried out using a Vankel dissolution apparatus following the USP Apparatus II paddle method. During all dissolution tests, to ensure sink conditions, only 10-30 percent of the saturation solubility of the drug was added to the dissolution apparatus. The appropriate amount of final drug prepa...

examples 1-8

[0069]The drug was cyclosporine, the organic was diethylether, and the concentration of the drug / organic mixture was 5.0 weight percent cyclosporine in diethylether. For the aqueous solution, Tween-80, a polyoxyethylene sorbitan monolaurate (ACROS) was a surfactant, or other excipient, which was used as the particle stabilizer. The drug / organic mixture was sprayed into 10 mL of aqueous solution at a rate of 1 ml / min. Table A lists processing parameters and the resulting particle sizes.

TABLE ADrug / organicAqueousSprayTween-80Medianpercenttemp.temptimeconc (wtparticleparticles Ex(° C.)(° C.)(min)percent)size (nm)median size165551014701126555101608643656510111146146565101759415706510170633670651017964377065101932508706520532214

examples 9-13

[0070]The drug was cyclosporine, the organic was diethylether, and the concentration of the drug / organic mixture was as shown below in Table B. For the aqueous solution, phosphatidyl choline (10 wt percent), a Sigma egg lecithin, 60 percent pure, was a surfactant, or other excipient, used as a particle stabilizer. The drug / organic mixture was sprayed into 10 mL aqueous solution at a rate of 1 ml / min. The temperature of the aqueous solution is 75° C., while the drug / organic mixture was sprayed into the aqueous solution at a temperature of 75° C. Table B lists some processing parameters and the resulting particle sizes.

TABLE BDrug concDrug conc in Spray in aqueousParticle sizeorganic solntime(mg / mlDrug / surfactantrangeEx(wt percent)(min)water)ratio(nm)912014.50.13135-3901021930.80.28120-5751151037.10.33 90-3001251034.90.32215-5901310629.70.30170

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Abstract

A method for preparing poorly water soluble drug particles is disclosed. The method comprises dissolving a drug in at least one organic solvent to form a drug / organic mixture, spraying the drug / organic mixture into an aqueous solution and concurrently evaporating the organic solvent in the presence of the aqueous solution to form an aqueous dispersion of the drug particles. The resulting drug particles are in the nanometer to micrometer size range and show enhanced dissolution rates and reduced crystallinity when compared to the unprocessed drug. The present invention additionally contemplates products and processes for new drug formulations of insoluble drug particles having high dissolution rates and extremely high drug-to-excipient ratios.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 10 / 266,998 filed Oct. 8, 2002, which is a continuation-in-part of U.S. application Ser. No. 09 / 808,332 filed on Mar. 3, 2001 which claims priority to U.S. application Ser. No. 60 / 245,479 filed on Nov. 3, 2000, under Title 35 of the United States Code section 120.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to drug particles and methods for their preparation. More particularly, the present invention relates to the preparation of drug particles utilizing evaporative precipitation into aqueous solutions.STATEMENT OF FEDERALLY FUNDED RESEARCH[0003]None.INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC[0004]None.BACKGROUND OF THE INVENTION[0005]Bioavailability is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the deve...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/14A61K31/192A61K31/55A61K31/44A61K38/13A61K31/58A61K9/20A61K9/51
CPCA61K9/14A61K38/13A61K31/192A61K31/55A61K31/44A61K31/58A61K9/145A61K9/146A61K9/1652A61K9/5123A61K9/5138A61K9/5146
Inventor JOHNSTON, KEITH P.WILLIAMS, III, ROBERT O.CHEN, XIAOXIA
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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