CN111821309B

CN111821309B - Darunavir composition with improved dissolution rate

Info

Publication number: CN111821309B
Application number: CN202010367178.5A
Authority: CN
Inventors: 田芳; 高明; 陈明; 安妮
Original assignee: Nycrist Pharmatech Ltd
Current assignee: Nycrist Pharmatech Ltd
Priority date: 2020-04-30
Filing date: 2020-04-30
Publication date: 2021-08-24
Anticipated expiration: 2040-04-30
Also published as: CN111821309A

Abstract

The present invention relates to a composition with improved dissolution rate comprising a salt of darunavir and an acidic polymer. The darunavir-acid polymer salt composition has higher dissolution speed and better stability, and can be applied to the treatment of virus infection diseases, such as acquired immunodeficiency syndrome (HIV), viral hepatitis and coronavirus infection.

Description

Darunavir composition with improved dissolution rate

Technical Field

The invention relates to the technical field of pharmacy, in particular to a composition with improved dissolution rate.

Background

Darunavir, chemically [ (1R,5S,6R) -2, 8-dioxabicyclo [ 3.3.0-decan-6-yl-N- [ (2S,3R) -4- [ (4-aminophenyl) sulfonyl- (2-methylpropyl) amino ] -3-hydroxy-1-phenyl-butan-2-yl ] carbamate, having the following structural formula:

darunavir is an HIV protease inhibitor developed by a subsidiary of the american firms, and is often marketed for later use in the treatment of adult HIV-infected patients in combination with ritonavir and other antiretrovirals. A typical dose is 600mg orally (combined with ritonavir 100mg), twice daily; 800mg (combined with 100mg of Reidesvir) was administered orally twice daily to treatment naive patients. Later studies showed that darunavir has an in vitro inhibitory activity against the novel coronavirus (COVID-19).

Patents US7700645B2 and US2015/0203506a1 disclose various solvate forms of darunavir. Such as darunavir ethanol solvate, darunavir hydrate, darunavir methanol solvate, darunavir acetone solvate, darunavir methylene chloride solvate, darunavir ethyl acetate solvate, darunavir 1-ethoxy-2-propane solvate, darunavir anisole solvate, darunavir tetrahydrofuran solvate, darunavir isopropyl solvate, darunavir methanesulfonic acid solvate.

The commercially available darunavir tablets use darunavir ethanol solvate, which has poor water solubility despite the presence of polymorphic forms. In addition, ethanol molecules in the darunavir ethanol solvate can exchange with water molecules to form a new hydrate under the environment of 25 ℃ and proper relative humidity, and the transportation process has the risk of crystal transformation, which affects the bioavailability (European Journal of Pharmaceutical Sciences 2009,38, 489-.

The absolute bioavailability of darunavir alone orally is about 37% (Drugs 2005,65, 2209-. The absorption of solid oral drugs must take into account the rate at which the drug is released into the gastrointestinal tract, and the drug is usually first dissolved in the gastrointestinal tract to form a molecular state for absorption through the gastrointestinal mucosa. Thus, dissolution of the drug is a prerequisite for its absorption in the gastrointestinal tract. Meanwhile, as the circulation time of the medicine in the gastrointestinal tract is limited, the medicine must also ensure a certain dissolution rate so as to be absorbed more in the limited circulation time and achieve a certain bioavailability. For high dose drugs, increasing bioavailability can reduce the dosage administered, thereby reducing side effects due to high doses.

Patent US9624236B2 discloses amorphous forms of darunavir and processes for their preparation, but no description is given of its dissolution. The disclosed darunavir amorphous form contains a small amount of crystalline impurities, and recrystallization can be induced in the process of storing the medicament, so that the dissolution of the medicament is changed along with the storage time, and the quality of the medicament is influenced. For example, as described in European Journal of Pharmaceutical Sciences 2009,38, 489-. As is well known to those skilled in the art, although amorphous form can increase the dissolution rate, recrystallization of amorphous drugs due to molecular fluidity is one of the important reasons for the decrease in storage stability and quality stability of such drugs. Furthermore, the amorphous darunavir starts to have a glass transition at about 40 ℃, and there is still a risk of long-term stable storage of darunavir according to the relatively safe line given by the International Journal of pharmaceuticals 2015,495,312-317 that has a glass transition temperature higher than the storage temperature of 20 ℃.

A compound oral preparation of darunavir and TMC125 is disclosed in patent US2010/0190809a1, but does not relate to a solid dispersion of darunavir and excipients, and a solid dispersion is prepared using only TMC 125. Electrospray was used in Journal of Pharmacy and Pharmacology 2016,68,625-633 to dry separate a solid dispersion of darunavir and various excipients, but the obtained dispersion was not in an amorphous state, and thus no improvement in dissolution due to the amorphous state could be obtained. Darunavir solid dispersions prepared in the European Journal of pharmaceuticals and biopharmaceuticals 2018,130,96-107 have drug loadings of up to 30% and no study has been made on the stability of the dispersions. Notably, none of the above-mentioned literature patents relate to darunavir salified with an acidic polymer.

In view of the above, there is a continuing need in the art to develop improved solid oral dosage forms for antiviral drugs such as darunavir that have superior dissolution rates to enhance bioavailability while having certain stability. Meanwhile, there is a need in the art to improve the dissolution rate of darunavir and to increase its physical stability.

Disclosure of Invention

The technical problem to be solved by the present invention is to provide a darunavir composition with improved dissolution rate.

The technical scheme adopted by the invention for solving the technical problems is as follows: a composition having improved dissolution rate is constructed comprising a salt of darunavir and an acidic polymer.

Preferably, said darunavir is dispersed in said acidic polymer at the molecular level.

Preferably, the darunavir-acidic polymeric salt is an amorphous dispersion and remains in the amorphous state for at least 2 months of accelerated stability testing (40 ℃, 75% relative humidity).

Preferably, the release of the darunavir acidic polymer salt composition for 2.5 minutes in a dissolution test is at least 2 times that of the control composition, and the time required for the darunavir acidic polymer salt composition to reach 80% release is at least 1 times shorter than that of the control composition.

Preferably, the control composition is one of the following ranavir solvates:

darunavir ethanol solvate, darunavir hydrate, darunavir methanol solvate, darunavir acetone solvate, darunavir methylene chloride solvate, darunavir ethyl acetate solvate, darunavir 1-ethoxy-2-propane solvate, darunavir anisole solvate, darunavir tetrahydrofuran solvate, darunavir isopropyl alcohol solvate, darunavir methanesulfonic acid solvate.

Preferably, the darunavir-acidic polymer salt composition is an oral dosage form.

Preferably, the darunavir acidic polymer salt composition comprises a weight ratio of darunavir to acidic polymer of 20:1 to 1:20, or the darunavir acidic polymer salt composition comprises a weight ratio of darunavir to acidic polymer of 10:1 to 1: 10.

Preferably, the acidic polymer is included in a single dose in a weight range of one of 1mg to 10g, 20mg to 1g, 20mg to 400 mg;

the single dose comprises darunavir in a weight range of one of 1mg to 800mg, 20mg to 600mg, 1mg to 200mg, 1mg to 100mg, 1mg to 30 mg.

Preferably, the acidic polymer is one of the following:

hydroxypropylmethylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP) and methylcellulose acetate phthalate (MCAP).

Preferably, the darunavir acidic polymer salt composition further comprises one or more pharmaceutically acceptable excipients selected from colloidal silicon dioxide, lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, diluents, flavoring agents, binders, film-forming polymers, antioxidants, light stabilizers, radical scavengers, surfactants, pH adjusters, drug complexing agents, and stabilizers against microbial attack, or combinations thereof.

The composition with improved dissolution speed for implementing the invention has the following beneficial effects: the darunavir-acid polymer salt composition has higher dissolution speed and better stability, and can be applied to the treatment of virus infection diseases, such as acquired immunodeficiency syndrome (HIV), viral hepatitis and coronavirus infection.

Drawings

The invention will be further described with reference to the accompanying drawings and examples, in which:

fig. 1A is darunavir of the present invention: a comparison of infrared spectra of a region of HPMCP salt composition, darunavir, a physical mixture of HPMCP, darunavir free base, and HPMCP;

fig. 1B is darunavir of the present invention: a comparison of the infrared spectra of the HPMCP salt composition, darunavir, a physical mixture of HPMCP, darunavir free base, and HPMCP in another region;

fig. 2 is darunavir of the present invention: a graph comparing dissolution measurements for the HPMCP salt composition and darunavir ethanol solvate;

FIG. 3 is an X-ray powder diffraction pattern of a HPMCP salt of darunavir of the present invention measured after spray drying preparation;

FIG. 4A is a differential scanning calorimetry trace of a HPMCP salt of darunavir of the present invention;

fig. 4B is a differential scanning calorimetry plot of HPMCP.

Detailed Description

For a more clear understanding of the technical features, objects and effects of the present invention, embodiments of the present invention will now be described in detail with reference to the accompanying drawings.

The composition having an improved dissolution rate in a preferred embodiment 1 of the present invention is a salt comprising darunavir and an acidic polymer.

Adding the darunavir free base and the acidic polymer into a solvent, forming an ionic bond between the basic darunavir and the acidic polymer, and drying to obtain the darunavir-acidic polymer salt composition.

The darunavir-acid polymer salt composition has higher dissolution speed and better stability, and can be applied to the treatment of virus infection diseases, such as acquired immunodeficiency syndrome (HIV), viral hepatitis and coronavirus infection.

The darunavir acidic polymer salt composition has a 2.5 minute release in a dissolution test that is at least 2 times that of the control composition, and the time required for the composition to reach 80% release is at least 1 times shorter than that of the control composition.

Preferably, the control composition is one of the following ranavir solvates:

The composition releases at least 80% of the darunavir within 5 minutes in a dissolution test.

The ionic bond reduces the fluidity of the darunavir molecule, and can explain that the composition has better physical stability because the amorphous composition is difficult to recrystallize.

Darunavir acidic polymer salts are amorphous dispersions that remain amorphous, i.e. maintain a certain physical stability, in an accelerated stability test (40 ℃, 75% relative humidity) for at least 2 months.

Darunavir is dispersed in the acidic polymer at the molecular level.

Preferably, the acidic polymer is one of the following:

In some embodiments, the darunavir free base and the acidic polymer are added to a mixed solvent of methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is 1:1, in other embodiments the volume ratio of methanol to dichloromethane can be other, and in other embodiments other solvents or solvent combinations that can dissolve both the darunavir free base and the acidic polymer can be used.

For example, by dissolving 1.2g of an acidic polymer (e.g., HPMCP) in a volume of solvent by magnetic stirring, then adding and dissolving 0.87g of darunavir ethanol solvate, drying the solution resulting in a darunavir: acidic polymer salt to obtain a darunavir salt containing 40% by mass of darunavir: an acidic polymer salt composition.

In some embodiments, 1mg to 10g of the acidic polymer and 0.87g of the darunavir solvate are dissolved per 100mL of solvent, in other embodiments 20mg to 1g of the acidic polymer is dissolved per 100mL of solvent by magnetic stirring; in other embodiments, 20mg to 400mg of the acidic polymer is dissolved per 100mL of solvent.

Further, spray-drying and separating by a spray dryer equipped with inert gas circulation; separated by a cyclone, a 50mL blue cap flask can be fitted directly to the cyclone for product collection.

The parameter settings for the spray-drying process are shown in table 1.

TABLE 1

After spray drying, the product was dried in an oven at 50 ℃ under reduced pressure for 1 hour to remove excess solvent, after which Thermal Gravimetric Analysis (TGA) was used to determine the solvent residue in the product. The physical state of the salt was then determined by XRPD and the results are shown in figure 3.

Further, in some embodiments, the darunavir acidic polymer salt composition comprises a weight ratio of darunavir to acidic polymer of 20:1 to 1:20, preferably the darunavir acidic polymer salt composition comprises a weight ratio of darunavir to acidic polymer of 10:1 to 1: 10.

Further, in some embodiments, the weight range of the acid polymer in a single dose is from 1mg to 10g, from 20mg to 1g, from 20mg to 400mg, and the weight range of the darunavir in a single dose is from 1mg to 800mg, from 20mg to 600mg, from 1mg to 200mg, from 1mg to 100mg, from 1mg to 30 mg.

Darunavir the acidic polymer salt composition further comprises one or more pharmaceutically acceptable excipients selected from colloidal silicon dioxide, lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, diluents, flavoring agents, binders, film forming polymers, antioxidants, light stabilizers, free radical scavengers, surfactants, pH adjusters, drug complexing agents, stabilizers against microbial attack, or combinations thereof.

Preferably, the darunavir-acidic polymer salt composition may be prepared into an oral dosage form.

In the following measurement and experimental examples, the acidic polymer was selected to be hydroxypropylmethylcellulose phthalate (HPMCP).

Example 2: and (3) measuring the content of the darunavir:

agilent 1260 model liquid chromatograph, agilent C18(15 × 0.46mm) column, using acetonitrile: 1 part of water: 1 is a mobile phase, the sample injection amount is 20 mu L, the flow rate is 1mL/min, and the ultraviolet detection wavelength is 267 nm.

Taking a proper amount of darunavir ethanol solvate, precisely weighing, adding mobile phase for dissolving, quantitatively diluting to prepare a solution containing about 10 mu g of darunavir ethanol solvate per 1mL, using the solution as a reference solution, precisely weighing 20 mu L of darunavir ethanol solvate, injecting the solution into a liquid chromatograph, and recording a chromatogram.

Taking a proper amount of the darunavir and acidic polymer salt composition prepared in the example 1, the weight percentage of the darunavir and acidic polymer salt composition in the darunavir and acidic polymer salt composition is about 40% by measuring according to the peak area by an external standard method.

Example 3: infrared spectrometry

A fourier transform infrared spectrometer (shimadzu) was used, matched with an attenuated internal reflectance accessory equipped with diamond crystals.

The spectrum collection range is 4000-650cm < -1 >, the scanning is carried out for 32 times, and the spectral resolution is 4.0cm < -1 >. Measurements were made with an air blank before recording the spectra for each sample.

In the present disclosure, the term "mixture" or "physical mixture" refers to a simple physical mixture of darunavir and HPMCP obtained by combining the dried components and physically stirring them together.

As is known in the art, the mixed powders do not substantially change the physical form of the drug, e.g., its crystalline or amorphous characteristics, and the mixed powders are not intended to produce an amorphous drug/polymer dispersion.

The darunavir acid polymer salt composition prepared in example 1 was subjected to infrared spectroscopy and compared with the infrared spectroscopy of 40% darunavir acid polymer physical mixture, darunavir free base, and HPMCP, and further, the darunavir acid polymer salt composition was selected from the darunavir HPMCP salt composition.

As shown in FIG. 1A, in the region of 3500-3150 cm-1, the chosen darunavir-HPMCP salt composition has fewer characteristic peaks than the physical mixture, which is caused by broadening and overlapping of the peaks of the N-H stretching movement caused by hydrogen bonds formed by-OH and-NH in the molecule.

Characteristic peaks around 3250cm-1, both in free base and in physical mixture, shifted in darunavir HPMCP salt compositions due to-NH in the darunavir molecule₂Protonation to form-NH₃ ⁺Thereby, the effect is achieved.

In FIG. 1B, both the free base and the physical mixture had-NH at 1647cm-1₂(ii) a distorted vibrational signature, but selected darunavir HPMCP salt composition is free of-NH at about 1647cm-1₂The deformation vibration characteristic peak has a characteristic peak at about 1530cm-1 and a broad peak at 1629 cm-1.

The broad peak of the composition at 1629cm-1 is-NH on the one hand₃ ⁺Caused by the presence, on the other hand, of-COO after salification of the acidic polymer^-Asymmetric stretching results, or both.

In addition, the broad peak of the composition in the vicinity of 1530cm-1 is represented by-NH₃ ⁺Is generated.

FIG. 1 results, binding to-NH in darunavir molecules₂And the pKa of-COOH in the acidic polymer HPMCP, the ionic bond is formed between the darunavir and the acidic polymer HPMCP, so that the fluidity of the darunavir molecule is reduced, and the composition can be explained to be amorphous, difficult to recrystallize and have better physical stability.

Example 3: dissolution test

The darunavir acidic polymer salt composition prepared in example 1 was subjected to dissolution test, and a darunavir HPMCP salt composition was selected.

27mg of darunavir, an acidic polymer salt, prepared in example 1 were manually filled into a size 1 gelatin capsule.

Another 11.7mg of darunavir ethanol solvate was manually filled into a size 1 gelatin capsule as a control group. According to the second method of dissolution determination method of "Chinese pharmacopoeia" 2015 edition, the dissolution medium is 900mL of 0.5% SDS aqueous solution (5g SDS is completely dissolved by 1000mL deionized water), the temperature is kept at 37 +/-0.5 ℃, the rotating speed of the rotating pulp is adjusted to 150 r/min, and the operation is carried out according to the method.

1mL of the sample was taken at 2.5, 5, 10, 15, 20, 30, 45 and 60min (and an equal amount of isothermal dissolution medium was added at the same time), and the sample was filtered through a 0.45 μm microfiltration membrane to prepare a sample solution.

Precisely measuring 20 μ L, injecting into a liquid chromatograph, testing according to the conditions in example 2, recording chromatogram, calculating the release of each sample at different time according to peak area by external standard method, and averaging 3 results of parallel tests in each group (see fig. 2).

The result shows that the dissolution rate of the darunavir ethanol solvate is 32.7 percent in 2.5min and reaches more than 80 percent in 15min, while the dissolution rate of the darunavir-HPMCP salt composition reaches 73.0 percent in 2.5min and reaches more than 80 percent in 5 min.

Example 4: x-ray powder diffraction (XRPD)

X-ray powder diffraction was carried out using a Dutch Pasnake X' Pert sharp X-ray powder diffractometer (PW3040/60) using Cu-Ka radiation at a wavelength of

The divergence slit 1/8 degrees, the X-ray light tube voltage 45kV, the X-ray light tube current 40mA, the scanning range 2-40 degrees (2 theta), the step size 0.0260 degree, and the scanning time 78.7950s per step.

The samples were plated on sample trays for testing, Data acquisition software X' Pert Data Collector, Data review software HighScore Plus.

The physical state and the physical stability of the darunavir acidic polymer salt are measured, and the darunavir HPMCP salt is selected. Fig. 3 is an X-ray powder diffraction pattern of daphnavir, HPMCP salt, isolated immediately after spray drying preparation, showing a diffuse peak with no sharp diffraction peak, confirming that the product is amorphous.

50 mg/sample of darunavir HPMCP salt was dispensed into glass vials and stored in a climate chamber at 40 ℃/75% RH without lid to test physical stability over time.

XRPD sampling was performed at time points of 7 days, 14 days, 1 month and 2 months and diffraction patterns were obtained using the XRPD method described above. The composition remained completely amorphous throughout the study, i.e., no diffraction peaks were shown in the diffractogram at any point in time.

Example 5: differential Scanning Calorimetry (DSC)

This was done in a TA Instruments Q2000 differential scanning calorimeter using a sealed disk apparatus.

Samples (approximately 1-3mg) were weighed in aluminum pans, capped with Tzero, and transferred to the instrument for measurement, which was purged with nitrogen at 50 mL/min.

Data were collected between 25 ℃ and 210 ℃ at a heating rate of 8 ℃/min, modulated to an amplitude of ± 0.85 ℃/40 seconds.

The endothermic peak was plotted downward and the data was analyzed by TA Universal Analysis. In the DSC chart, the abscissa represents Temperature (DEG C) and the ordinate represents the Heat Flow (W/g) released per unit mass of a substance.

The acidic polymer salt of darunavir (HPMCP salt) of the present invention shown in fig. 4A has a unique and different glass transition temperature from the acidic polymer (HPMCP) shown in fig. 4B, which is much higher than room temperature and the amorphous glass transition temperature (Tg) of darunavir, which facilitates long-term stable storage of the composition of the present invention, while illustrating that darunavir of the present invention is dispersed in the acidic polymer at a molecular level.

As is well known to those skilled in the art, the differential scanning calorimetry curve has experimental errors, and the position and peak value of the endothermic peak may be slightly different between the instrument parameters, equipment model and sample preparation process, and the experimental error or difference may have a value of 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the peak position of the DSC endothermic peak cannot be regarded as absolute.

One assessment of the potential utility of a pharmaceutical oral dosage form is the dissolution profile (dissolution profile) observed after placing the dosage form in a dissolution apparatus used in standard chinese pharmacopoeia. When placed in a dissolution medium, a variety of factors can affect the dissolution profile of the dosage form. These factors include water solubility, dissolution rate, solvent, agitation rate and dosage strength, among others. Water solubility is one of the most important of these factors.

It is understood that the compositions of the present invention have certain functions. Certain structural requirements for performing the disclosed functions are disclosed herein, and it should be understood that a variety of structures exist that can perform the same functions associated with the disclosed structures, and that such structures will generally achieve the same results.

Applications of

The darunavir-acidic polymer salt composition of the present invention may further comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers refer to sterile aqueous or non-aqueous solutions, dispersions, suspensions or creams, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

The darunavir-acidic polymer salt composition of the present invention may comprise the salt of darunavir as an active ingredient, a pharmaceutically acceptable carrier, and (optionally) other therapeutic ingredients or adjuvants. The compositions of the present invention are suitable for, but are not limited to, oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) modes of administration. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be added to prevent the unwanted growth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must flow effectively for ease of injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; therefore, it should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as aerosols, creams, ointments, lotions, dusting powders, mouthwashes, gargles and the like. In addition, the composition may be in a form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods using the compounds of the present invention or pharmaceutically acceptable salts thereof. For example, a cream or ointment having a desired consistency is prepared by mixing a hydrophilic material and water and about 5 wt% to about 10 wt% of the compound.

The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably, the compositions form unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may conveniently be formed by first mixing the composition with the softened or molten carrier, followed by cooling and shaping in a mould.

In yet another aspect of the present invention, the pharmaceutical composition of the present invention may comprise darunavir salified with an acidic polymer selected from the group consisting of: hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose Acetate Trimellitate (CAT), Cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP) and Methyl Cellulose Acetate Phthalate (MCAP), and may further contain one or more other therapeutically active compounds.

The pharmaceutical carriers useful in the present invention may be solid, liquid or gaseous. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. can be used to form oral liquid preparations such as suspensions, liqueurs, solutions; carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral formulations, which employ solid pharmaceutical carriers. Alternatively, the tablets may be coated by standard aqueous or non-aqueous techniques.

Tablets comprising the composition of the invention may be prepared by compression or moulding, optionally together with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine a free-flowing active ingredient, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

In addition to the above-described carrier ingredients, the above-described pharmaceutical preparations may include one or more other carrier ingredients, as appropriate, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing the compounds of the present invention and/or pharmaceutically acceptable salts thereof may also be prepared in the form of a powder or liquid concentrate.

In yet another aspect of the present invention, the composition further comprises one or more excipients selected from the group consisting of colloidal silica, lubricants, fillers, disintegrants, plasticizers, colorants, emulsifiers, diluents, flavoring agents, binders, film-forming polymers, antioxidants, light stabilizers, free radical scavengers, surfactants, pH adjusting agents, pharmaceutical complexing agents, and stabilizers against microbial attack, or combinations thereof.

The compositions of the present invention may be used in a variety of forms for oral administration, usually together with a pharmaceutically acceptable diluent or carrier. Exemplary dosage forms are powders or granules which can be taken orally as a dry powder directly or by addition of water to form a paste, slurry, suspension or solution; or tablet, capsule or pill. Various additives may be mixed or granulated with the compositions of the present invention to form materials suitable for use in the dosage forms described above. Potentially beneficial additives are generally classified into the following categories: other matrix materials or diluents, surfactants, drug complexing or solubilizing agents, fillers, disintegrants, binders, lubricants, and pH adjusting agents (e.g., acids, bases, or buffers).

Non-limiting examples of other matrix materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate and starch.

Non-limiting examples of surfactants include sodium lauryl sulfate and polysorbate 80. The surfactant can be fatty acid and alkyl sulfate; such materials can be advantageously used to increase the rate of dissolution by promoting wetting, and can also inhibit crystallization or precipitation of the drug by mechanisms such as complexation, clathrate formation, micelle formation or adsorption on the surface of the solid drug, crystalline or amorphous forms. These surfactants can comprise up to 25% of the disclosed compositions.

Non-limiting examples of drug complexing or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid and cyclodextrin.

Non-limiting examples of disintegrants include sodium starch glycolate, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and croscarmellose sodium.

Non-limiting examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and gelatin.

Non-limiting examples of lubricants include magnesium stearate and calcium stearate.

Non-limiting examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; and buffers typically comprising an acid and a salt mixture of the acid.

For oral administration, the pharmaceutical compositions suitable for use in the present invention may take a variety of forms including solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets may contain various excipients such as matrix materials, fillers, diluents, surfactants, drug complexing agents, solubilizers, disintegrants, binders, lubricants and pH adjusters as described above. Hard gelatin capsule formulations typically comprise a drug in tablet form as described above, a polymer and excipients. When aqueous suspensions and/or cordials are desired for oral administration, the compounds of the invention may be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as various similar compositions such as water, ethanol, propylene glycol, glycerol, and the like.

In yet another aspect of the invention, the composition is formulated for parenteral administration. In yet another aspect of the invention, the composition is formulated for inhalation. In yet another aspect of the invention, the composition is formulated for oral administration. In yet another aspect of the invention, the composition is formulated for topical administration.

The compositions and solid dosage forms provided by the present invention have a faster dissolution rate and better stability than control compositions comprising darunavir not salified with an acidic polymer.

It is to be understood that the above-described respective technical features may be used in any combination without limitation.

The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.

Claims

1. A darunavir amorphous dispersion with improved dissolution rate, which is characterized in that darunavir free base and hydroxypropyl methylcellulose phthalate (HPMCP) are added into a solvent, an ionic bond is formed between the alkaline darunavir and the hydroxypropyl methylcellulose phthalate (HPMCP), and the darunavir and hydroxypropyl methylcellulose phthalate (HPMCP) amorphous dispersion is obtained after drying.

2. The darunavir amorphous dispersion with improved dissolution rate according to claim 1, characterized in that it remains amorphous in an accelerated stability test at 40 ℃, 75% relative humidity for at least 2 months.

3. The darunavir amorphous dispersion with improved dissolution rate according to claim 1, characterized in that it is an oral dosage form.

4. The darunavir amorphous dispersion with improved dissolution rate according to claim 1, characterized in that the weight ratio of darunavir to hydroxypropylmethylcellulose phthalate (HPMCP) is 20:1 to 1: 20.

5. The darunavir amorphous dispersion with improved dissolution rate according to claim 1, characterized in that the weight ratio of darunavir to hydroxypropylmethylcellulose phthalate (HPMCP) is 10:1 to 1: 10.

6. The darunavir amorphous dispersion with improved dissolution rate according to claim 1 characterized in that the weight of hydroxypropyl methylcellulose phthalate (HPMCP) contained in a single dose ranges from 1mg to 10 g; the darunavir is contained in a single dose in a weight range of 1mg to 800 mg.

7. The darunavir amorphous dispersion with improved dissolution rate according to any of claims 1 to 6, characterized in that it further comprises one or more pharmaceutically acceptable excipients.