TW201309286A - Pharmaceutical composition comprising ketoprofen - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation of ketoprofen sodium salts in a hydrophilic solvent system suitable as a liquid fill composition. In another aspect, the invention also relates to a process for the preparation of the said pharmaceutical formulation and the use of the said formulation for preparing a medicament to treat inflammatory pains.

Description

Pharmaceutical composition comprising ketoprofen (KETOPROFEN)

The present invention relates to a stable pharmaceutical liquid composition for oral administration of ketoprofen sodium salt.

In particular, the present invention relates to an improved composition comprising a ketoprofen sodium salt and a pharmaceutically acceptable excipient, optionally encapsulated in a capsule.

Furthermore, the invention relates to a method of preparing the pharmaceutical composition and the use of the composition for the preparation of a medicament for the treatment of inflammatory pain.

Ketoprofen [2-(3-benzhydrylphenyl)propionic acid] is a non-steroidal anti-inflammatory drug (NSAID) that has long been recognized for its long-term approval since 1972 due to its analgesic, anti-fever and anti-inflammatory properties. Treats fever, pain and inflammation. Its molecular formula is C ₁₆ H ₁₄ O ₃ and its molecular weight is 254.29. The mechanism of action of ketoprofen is mainly related to the ability to inhibit the synthesis of prostaglandins in humans. Ketoprofen is typically formulated and administered as a racemic mixture of the R and S enantiomers, both in equal amounts per weight.

Ketoprofen has certain advantages over aspirin, acetaminophen and ibuprofen: it is more widely accepted that pain relief is more effective and plays an important role. Ketoprofen is generally administered orally in the form of a conventional lozenge or a tablet coated with a gastric-resistant coating, or rectally or by injection or topical ingestion. Ketoprofen is commercially available as a lozenge under the trade name Orudis KT®. The conventional dosage form of the drug is rapidly and almost completely absorbed from the gastrointestinal tract by oral administration, and a peak plasma concentration occurs within 1 hour to 3 hours.

For drugs belonging to the class of NSAIDs such as ketoprofen and its pharmaceutically acceptable salts, it is important that the drug remain in the dissolution phase or in the size of the micelles after reaching the stomach. This helps the drug to absorb faster and provides an earlier onset time, which is not the case in the conventional lozenge dosage form, because once the tablet enters the stomach, it disintegrates into particles and the particles further disintegrate, and the drug is exposed to the stomach. Under acidic conditions. Due to the subsequent series of activities, a lag time is generated which delays the earlier absorption of the drug. Longer absorption delays or longer absorption delays are not acceptable for diseases where it is desirable to have an analgesic effect that begins to benefit the patient.

FR 2 660 555 describes soft gelatin capsules for oral administration comprising a ketoprofen sodium salt dispersed in a fat-based carrier. A disadvantage of the use of such fat-based carriers is that the composition is not a clear true solution, and thus is an early onset time for ketoprofen, requiring a dissolution phase of the drug in a digestive apparatus.

No. 5,624,682 discloses a ketoprofen solution in a soft capsule comprising ketoprofen acid dissolved in polyethylene glycol, containing a quantity of neutralizing organic amine such that the pH of the solution is between 5 and 7. However, the pharmaceutical composition is not stable over time and causes high levels of impurities to form from ketoprofen.

Accordingly, it is an object of the present invention to develop a pharmaceutical composition of a ketoprofen sodium salt which provides a stable composition having an earlier or similar initial action time compared to prior art prior art.

Applicants have discovered that this goal can be achieved by providing an improved composition comprising a ketoprofen sodium salt and a pharmaceutically acceptable liquid hydrophilic carrier medium.

When designing the liquid carrier medium, the carrier medium containing the active agent must be reasonably designed and accurately prepared, and the composition may not even be slightly altered without irreversibly disturbing the system and destroying its beneficial properties. For example, if the carrier medium is slightly altered, the solubility of the composition changes and the active material precipitates. Applicants have discovered that encapsulation of such liquid formulations in soft gelatin capsules potentially provides a convenient means of administering such pharmacologically active substances without altering the carrier medium.

In addition, oral administration of ketoprofen can cause serious side effects, most notably gastrointestinal disorders such as dyspepsia, gastroduodenal bleeding, gastric ulcers and gastritis, especially after prolonged use. This is because the drug in the tablet dosage form remains fine in the stomach, which activates the adenosine triphosphatase proton pump, causing a stomach disorder. Thus, the use of a drug to maintain a particular carrier system design formulation that is dissolved in a solution state helps to counterbalance the gastric acidity. The form of ketoprofen syrup available in the commercial market is not preferred in terms of patient compliance because ketoprofen has a bitter taste.

The inventors of the present invention have recognized this need and have sought to circumvent these problems by developing rationally designed formulations to rapidly release the ketoprofen sodium salt. Ketoprofen in the form of a capsule also exhibits more patient compliance in addition to the advantages mentioned above, as the taste of the residual residue of the drug after swallowing is masked. Thus, the form of ketoprofen gelatin capsules is more widely accepted commercially than its previous delivery methods.

Accordingly, the present invention relates to a stable pharmaceutical composition for oral administration comprising a pharmaceutically effective amount of ketoprofen sodium salt, one or more hydrophilic The carrier, optionally with one or more buffers and/or acidifying or basifying agents, is employed to produce a palatable and stable formulation with rapid therapeutic effects.

Another object of the present invention is to provide a pharmaceutical formulation comprising a formulation of the invention, such as a soft capsule, a hard capsule, a two-piece capsule or a lozenge.

Another aspect of the present invention provides a method of preparing an oral pharmaceutical composition of the present invention, which comprises dissolving a drug in a suitable amount of a liquid hydrophilic carrier and bringing the pH to an acceptable range, thereby enhancing the formulation. Storage stability and shelf life.

The invention also relates to the use of a composition of the invention for the manufacture of a medicament for the treatment of inflammatory pain.

Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meaning commonly understood by one of ordinary skill. The meaning and scope of the terms should be clear; however, in the event of any potential ambiguity, the definitions provided herein take precedence over any dictionary or foreign definition. Unless the context requires otherwise, singular terms include plural and plural terms include the singular.

According to the invention, a stable formulation means a formulation which in particular exhibits a high resistance to recrystallization or decomposition of the sodium ketoprofen salt. Thus, after storage for one month or two months at 40 ° C and 75% humidity, the pharmaceutical compositions of the present invention do not exhibit any signs of crystallinity and remain as a clear solution of the ketoprofen substrate. Further, it means that the pharmaceutical composition of the present invention contains at least 99% (w/w) of the initial ketoprofen sodium salt after storage for one month or two months at 40 ° C and 75% humidity, and does not exhibit any Signs of high degree of decomposition, ie total ketoprofen sodium The impurity content was less than 1% by weight (as evidenced by HPLC analysis).

The present invention relates to a stable pharmaceutical composition for oral administration comprising a pharmaceutically effective amount of ketoprofen sodium salt, which is used to enhance the storage stability and shelf life of the drug in the dosage form by comprehensively determining the optimal conditions. Such as the correlation between the drug and the accompanying components, the selection of the optimum mixing ratio of the individual components, and the selection of the particular carrier medium, water content, and pH adjuster.

Accordingly, a first aspect of the invention is directed to a pharmaceutical liquid composition comprising a ketoprofen sodium salt.

In the compositions of the present invention, the ketoprofen sodium salt is present in an amount ranging from 1% to 15% by weight of the composition. More preferably, the ketoprofen sodium salt is present in an amount ranging from 6 wt% to 15 wt% of the composition.

The carrier used in the present invention is a liquid hydrophilic carrier. The term "hydrophilic carrier" means one or more of these pharmaceutical excipients which, when mixed with ketoprofen at pH 7.5 to 10, increases the water-soluble and hydrophilic lipophilic balance of ketoprofen in the carrier. The hydrophilic lipophilic balance (HLB) has a value of 10 to 18, preferably 11 to 16. According to the present invention, hydrophilic carriers include, but are not limited to, polyethylene glycol (such as PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG3000, PEG4000, PEG6000 or PEG8000), glycerin, propylene glycol, PEG 40 hydrogenated castor oil , polysorbate, glyceryl cocoate, PEG 6 caprylic/caprylin, poloxamer, labrafil, bismuth hexaethylene glycol-8 glycerides (Labrasol ^TM), polyethoxylated castor oil (Cremaphor ^TM EL), glycerol - group stearate or polyethylene glycol PEG-40 hydrogenated castor oil (Cremophor ^TM RH), ethoxylated fatty Alcohol (Brij) and sorbitan ester (Spans). Any of the above mentioned hydrophilic carriers can be used alone or in combination with one or more hydrophilic carriers. In a preferred embodiment of the invention, the liquid hydrophilic carrier medium is polyethylene glycol 600. In another preferred embodiment of the invention, the liquid hydrophilic carrier medium is a combination of polyethylene glycol 600 and octadecyl decyl polyethylene glycol-8 glyceride.

In the compositions of the present invention, the liquid hydrophilic carrier is present in an amount ranging from 80% to 95% by weight of the composition and more preferably in the range of from 85% to 95% by weight.

In another aspect, the invention relates to an orally administrable formulation comprising ketoprofen as an active agent and a carrier, wherein the weight of the ketoprofen sodium salt and the liquid hydrophilic carrier is preferably 1: 6 to 1:15. In a preferred embodiment of the invention, the weight ratio is from 1:12 to 1:15.

In order to ensure proper storage stability and shelf life of the pharmaceutical formulation and to improve its stability and shelf life, another criterion within the present invention is the pH of the ketoprofen sodium salt in a suitable pharmaceutical vehicle. The pH of the composition is in the range of 7.5 to 10 and more preferably 9.2 to 10.0. In a preferred embodiment, the composition has a pH of 9.5.

According to the invention, such pH values can be achieved, if desired, by the addition of suitable acidifying and basifying agents or in combination with suitable buffering agents.

In the compositions of the present invention, the acidulant and basifying agent are preferably present in an amount ranging from 0% to 1.5% by weight of the composition.

The alkalizing agent used in the present invention may be selected from the group consisting of calcium carbonate, magnesium hydroxide, gum arabic, calcium hydrogen phosphate, potassium hydroxide, sodium acetate, potassium phosphate, sodium carbonate, and the like. And / or a combination thereof. The inventors of the present invention observed (see examples) that a neutralized organic amine having a group consisting of ethanolamine cannot be used to obtain a formulation which is stable over time. The alkalizing agent is preferably potassium hydroxide.

The acidifying agent used in the present invention may be selected from the group consisting of acetic acid, lactic acid, ascorbic acid, citric acid, phosphoric acid, oxalic acid, calcium chloride, ammonium hydroxide, and the like, and/or combinations thereof. The acidifying agent is preferably citric acid.

The present invention also demonstrates various advantages regarding administration and suitable methods of administration. Another advantage of the present invention over prior art compositions is the rational design of ketoprofen oral formulations with measured other excipient components and the manufacture of orally administerable lozenges. The method can be easily scaled. In addition, due to the rationally designed oral formulation and its method of manufacture, the scalability factor does not affect the in vivo drug efficacy or its in vivo release profile.

The exact dose of active agent and particular formulation to be administered will depend on a number of factors, such as the condition to be treated, the duration of treatment required, and the rate of release of the active agent. For example, the amount of active agent required and its rate of release can be determined based on known in vitro or in vivo techniques to determine the length of time that a particular active agent plasma concentration maintains an acceptable therapeutic effect.

Another aspect of the present invention relates to a method of preparing a pharmaceutical preparation of the present invention comprising the sequential steps of: dissolving a ketoprofen sodium salt in a liquid hydrophilic carrier under stirring to obtain a homogeneous mixture; and then A sufficient amount of alkalizing agent is needed to adjust the pH.

Another aspect of the invention pertains to the use of a composition of the invention for the treatment of inflammatory pain. In particular, the composition of the invention can be used to relieve pain Pain and inflammation, including, for example, types of pain that are easy to treat, including but not limited to: toothache, headache (head pain), migraine, abdominal pain and pelvic pain, rheumatic pain, ankylosing spondylitis, acute joints and joints Peripheral conditions (bursitis, consumps, synovitis, tendonitis), fibrous tissue pain, fever, fever, influenza and common cold symptoms, sore throat, lower back pain, muscle pain (myalgia), Torticollis (sacral neck), joint pain, leg pain, contusion, sprain, tendonitis, tennis elbow, low back pain, joint pain, post-traumatic pain, sciatica, bursitis, fibrositis, painful musculoskeletal conditions, dysmenorrhea , swelling, mild phlebitis, spinal pain (spine pain), mild motor injury, varicose pain, varicose inflammation, abrasion (hematoma), acute, subacute and chronic severe pain (postoperative, tumor, myocardial Infarction, trauma, fractures) and acute pain from diagnostic and therapeutic measures.

In another aspect, the invention provides a soft gelatin capsule comprising a capsule shell comprising gelatin, a plasticizer, and other ancillary materials, if desired or as desired.

In developing the soft gelatin capsule ketoprofen formulations of the present invention, it must be recognized that the capsules are systems comprising a ketoprofen formulation and a gelatin shell for encapsulating the ketoprofen formulation. Thus, it is preferred not only to provide the desired pharmacological effect of the filled ketoprofen formulation, but it is also preferred that the gelatin shell formulation must be compatible with the ketoprofen formulation. Those skilled in the art will be aware of potential filler-shell interactions that can result in physical and chemical instability of the capsule. Thus, the use of gelatin shell formulations to form capsules for ketoprofen formulations is also preferred and is important to the present invention.

Gelatin shell capsules for soft gelatin capsules are generally prepared from raw gelatin and One or more ingredients are added which are added to plasticize the gelatin to achieve a suitable hardness for the design or better desired. Typical plasticizers include glycerin, sorbitol, sorbitan, and mixtures containing glycerin, sorbitan, and mannitol may also be utilized. In addition, other non-traditional ingredients can be used to plasticize the gelatin.

Thus, gelatin formulations suitable for use with the ketoprofen formulations of the present invention provide the requisite physical and chemical stability required.

A major problem with gelatin-based formulations is that upon aging, the dissolution is significantly reduced due to cross-linking of the gelatin-containing product. Crosslinking forms an extremely thin and tough rubbery water insoluble swollen film, also known as a film. The membrane acts as a barrier and limits drug release. Drugs such as ketoprofen sodium salt have a tendency to react with gelatin and induce cross-linking, so there is a high possibility that the dissolution is lowered during the stability study. The inventors of the present invention have surprisingly overcome this cross-linking of gelatin by the addition of certain weak acids in combination with glycine. In a particular embodiment of the invention, the weak acid used in the invention is tartaric acid, citric acid or a combination thereof. The amount of weak acid may range from 0.1% (w/w) to 1.0% (w/w) of the gelatin shell formulation.

Preferred gelatin formulations for constructing soft gelatin capsules containing the ketoprofen formulations of the present invention comprise from about 30% (w/w) to about 58% (w/w), preferably but not limited to 40% to 45. Gelatin in the range of % and plasticizer in an amount ranging from about 10% to about 35%, preferably but not limited to from 15% to 25%. Suitable plasticizers for use with preferred capsule formulations include sorbitol (Special MDF 85, European Pharmacopoeia grade). When sorbitol is used alone as a plasticizer, the amount may range from about 15% to about 40%.

The capsule formulation may also include other suitable additives, such as preservatives and/or colorants, for stabilizing the capsule and/or imparting specific characteristics to the capsule, such as color or appearance. Pharmaceutically acceptable preservatives can include, for example, methylparaben and propylparaben. The gelatin shell color can be imparted using FD&C and/or D&C dyes. Exemplary dyes include, but are not limited to, Tartrazine yellow, Azura red, and the like. An opacifying agent such as titanium dioxide and/or iron oxide may be used to color and/or render the capsule opaque.

The present invention contemplates the use of a coating agent which may include a non-functional or enteric coating agent such as a cellulose based polymer, film coating agent or other coating agent known to those skilled in the art.

The invention also contemplates the use of other pharmaceutical excipients such as binders, disintegrants, diluents, lubricants, plasticizers, penetration enhancers, and solubilizers known to those skilled in the art. Such other additives include antioxidants, preservatives, chelating agents, complexing agents, viscosity modifiers, tonicity agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, and mixtures thereof. The amount of such additives can be readily determined by those skilled in the art in accordance with the particular properties desired.

The pharmaceutical compositions of the present invention can be prepared by conventional methods well known to those skilled in the art. However, the particular method of preparation will depend on the final dosage form. The hydrophobic therapeutic agent can be dissolved in one or more carriers. The composition can be prepared by simply mixing or stirring the components to form a concentrate. The stirring process can be assisted by heating as needed. The hydrophobic therapeutic agent can be present in a first amount dissolved by the carrier and, if desired, in a second amount in the carrier. Should emphasize that adding each The order of the components is generally not critical and can be changed as conveniently.

According to the present invention, the preparation of a pharmaceutical formulation based on the ketoprofen sodium salt in a soft gelatin capsule is carried out in two stages.

Accordingly, a therapeutically active amount of the ketoprofen sodium salt is dissolved in a suitable amount of a pharmaceutically suitable vehicle to bring the pH to an acceptable range of higher stability and to oscillate the mixture until a clear true solution is achieved. If deemed useful, a small amount of sterile water, propylene glycol, glycerin, preservatives or other additives may be added to the solution, such as additives typically used in the formulation of pharmaceutical compositions in the form of soft capsules.

Once the basic principles of achieving the pharmaceutical formulations of the present invention in the form of soft gelatin capsules are understood, the pharmaceutical formulation experts can change the method criteria to suit particular needs without difficulty.

Another object of the present invention is to provide a method of administering a pharmaceutically active ingredient to a host to increase the bioavailability of ketoprofen comprising the steps of: a) providing a stable gelatin composition of the present invention for oral administration; b) administering the composition to the host for ingestion whereby the composition contacts the biological fluid of the human body and produces a faster onset time.

The core component of a typical formulation of the invention may comprise: - 1% (w/w) to 15% (w/w) of ketoprofen sodium salt; - 80% (w/w) to 95% (w/w One or more liquid hydrophilic carriers; wherein the pH of the composition is between 7.5 and 10.

The gelatin shell component of a typical formulation of the invention may comprise: - 35% (w/w) to 50% (w/w), more preferably 40% to 44% gelatin; - 15% (w/w) to 30 % (w/w), more preferably 15% to 25% sorbitol; - 0.1% (w/w) to 10% (w/w) of the colorant; - 0.1% (w/w) to 10% (w/w) of tartaric acid; - 10% (w/w) to 50% (w/w) purified water.

The drug release rate of the composition of the present invention filled in gelatin capsules is preferably greater than 85% in 10 minutes when tested in 100 ml of pH 7.4 phosphate buffer (without enzyme) at 100 RPM and 37 °C. Ketoprofen sodium salt.

In use, the methods and compositions of the present invention encompass a number of important advantages, including: resistance to denaturation at the target site and improved delivery: the compositions of the present invention are unexpectedly resistant to deformation and the compositions of the present invention are rendered precipitated Minimized and unexpectedly provides improved delivery of the therapeutic agent to the absorption site. It is believed that the delivery of this improvement results in a faster onset of action of the therapeutic agent.

Generality: The compositions of the present invention can be carefully tailored and adjusted for the polarity and functionality of the therapeutic agent without compromising the improved dissolution, delivery, and other advantages as described above.

Preparation ease: The method of the present invention provides a composition that readily dissolves the hydrophobic therapeutic agent, thereby saving costly manufacturing and human resources.

In another aspect of the invention, a method of preparing a pharmaceutical composition is provided. The method comprises incorporating the active ingredient ketoprofen into a carrier. In addition, if appropriate, an emulsion suitable for the formulation of a pharmaceutical excipient is added. In a preferred embodiment, the carrier is continuously agitated with the active ingredient. Excipients are then mixed.

Soft gelatin capsules are manufactured by a rotary stamping process using gelatin in a conventional method. Dry gelatin granules are combined with water and a suitable plasticizer, and the combination is Mix and heat under vacuum to form a molten gelatin mass. The gelatin mass remains in its melting stage while being formed or cast into a film or strip on a casting wheel or drum. The film or strip is fed between the wedge and the rotating encapsulation mold. In the encapsulating mold, a capsule is simultaneously formed from the film or strip in the groove in the mold. The ketoprofen-containing composition is filled in a soft gelatin capsule using any conventional method. The capsule is then cut and sealed. When filling and cutting the capsule, a seal is formed via a combination of pressure and heat.

The invention is further illustrated in the following examples. It is to be understood that the examples are merely illustrative of the preferred embodiments of the invention. From the above discussion and the examples, those skilled in the art can determine the essential characteristics of the present invention, and various changes and modifications can be made to the various uses and conditions without departing from the spirit and scope of the invention. .

Instance

Although the present invention has been described in connection with the specific embodiments, it will be apparent Accordingly, the present invention is intended to embrace all such modifications and alternatives

In the examples below, the composition ratios show weight ratios.

Example 1: Formulation of Soft Ketoprofen Capsules

The active agent ketoprofen substrate was dissolved in PEG ethylene glycol 400 in a blender with constant agitation to form a clear solution. If necessary, the pH is adjusted using potassium hydroxide until a pH of 7.5 to 10.0 is obtained. The components of the pharmaceutical formulations of the present invention have a form suitable for encapsulation. The formulation is encapsulated in a soft gelatin capsule according to a method known per se to those skilled in the art.

Example 2: Formulation of soft ketoprofen capsules

The active agent ketoprofen substrate was dissolved in PEG ethylene glycol 600 in a blender with constant agitation to form a clear solution. The formulation is encapsulated in a soft gelatin capsule according to a method known per se to those skilled in the art.

Example 3: Formulation of soft ketoprofen capsules

The active agent ketoprofen substrate was dissolved in PEG ethylene glycol 400 in a blender with constant agitation to form a clear solution. If necessary, the pH is adjusted using potassium hydroxide until a pH of 7.5 to 10.0 is obtained. The components of the pharmaceutical formulations of the present invention have a form suitable for encapsulation. The formulation is encapsulated in a soft gelatin capsule according to a method known per se to those skilled in the art.

Example 4: Comparative Stability Study of Compositions of the Invention

Different fill compositions (A to F) were tested. Stress tests were performed on each batch of the filling composition, including temperature (40 ° C) (for accelerated testing) and humidity (75% RH). The test allows evaluation of the sensitivity of the hydrolysis of the ketoprofen sodium salt and, in particular, the formation of cyclic ester impurities of ketoprofen.

The stability of the liquid formulation fill filled in the glass vial was investigated and measured after one month (1 M) and two months (2 M) after the study under these accelerated conditions.

The results obtained are as follows:

In the above table, the impurity content is expressed by weight based on the ketoprofen sodium salt.

The stability study showed that for compositions A, B, C and D, after 2 months of study at 40 °C ± 2 °C / 75% RH ± 5% RH under accelerated storage conditions, the impurities in the analysis The content varies significantly from its initial value (from less than 0.1% w/w to more than 0.2% w/w). These degradation products are outside the acceptance criteria.

On the other hand, the total impurity content of Composition E and Composition F of the present invention remains stable, less than 0.1% (w/w), and is therefore acceptable.

Example 5: Comparative in vitro dissolution studies and in vivo bioavailability of compositions of the invention

The dissolution profile of the composition of Example 3 was compared to the dissolution profile of the Toprec® product 25 mg tablet.

method: a) Dissolution conditions:

Device: agitating paddle with sinker

Speed: 100 RPM

Dissolving medium: 900 ml

Temperature: 37 ° C ± 0.5

Time point: 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes or the required time point.

b) Dissolving medium composition: pH 7.4 phosphate buffer (without enzyme) c) Test procedure:

One capsule was weighed and placed in each of the six dissolution vessels containing the dissolution medium. After the specified time point, from the surface of the dissolution medium A 10 ml aliquot was taken from the area between the top of the rotating blade and the vessel wall at a distance of not less than 10 mm. The solution was filtered through a 0.45 μm nylon 66 filter paper.

d) Chromatographic conditions:

Equipment: Liquid chromatograph equipped with a UV detector

Column: X'terra, C18, 150 mm × 4.6 mm, 5 μm or equivalent column

Column temperature: 35 ° C

Flow rate: 1.2 ml / min

Detect UV wavelength: 260 nm

e) Instrument

a. Verified automatic dissolution system

b. HPLC system containing pump, autoinjector, UV detector

result: In vitro dissolution profile:

The dissolution profile of the composition of Test Example 2 was tested.

The above experimental results revealed that for the composition of the present invention, 92% (w/w) of the dissolved ketoprofen sodium salt was released after 15 minutes.

Pharmacokinetic simulation:

The pharmacokinetic blood profile of the pharmaceutical composition of the present invention was calculated using a simulation program.

Developing a mathematical model (simulation software available from Gastroplus ^TM Simulations Plus, Incorporated the obtained) to explore in vivo release can meet certain objectives of the input rate of one dosage form of ketoprofen. Gastroplus® is a computer program that simulates the absorption and pharmacokinetics of orally administered drugs. The basic model is the Advanced Compartmental Absorption and Transit (ACAT) model, which is an extension of the work originally performed by Gordon Amidon and Lawrence Yu. See LXYu, "An Integrated Model for Determining Causes of Poor Oral Drug Absorption". Pharm. Res.. 16:1883-7 (1999) and B. Agoram, WSWoltosz and MBBolger, "Predicting the impact of physiological and biochemical processes on oral Drug bioavailability", Advanced Drug Delivery Reviews, 50: S41-S67 (2001).

Several different screening methods in the Gastroplus software can be modified to produce an optimal dosing profile.

The compound screening method has the following parameters (which can be changed): Dosage form: IP solution

Initial dose (mg): 25 (example)

Subsequent dose (mg): 0

Dosing interval (hours): 0

Dosage volume (mL): 250

Reference solubility pH: 2

Solubility (mg/mL, at pH=2): 0.118

Average precipitation time (seconds): 90

Diffusion coefficient (cm ² × 10 ⁵ ) = 0.432

Drug particle density (g/mL): 1.253

Peff (effective permeability) (cm/s × 10 ⁴ ): 8.7

Simulation Peff × 10 ⁴ (human): 8.7

Molecular weight = 254.29

Reference Log D=3.16, at pH=1

Particle size: R=25.00, D=50.00

pKa: 4.6 / solubility factor: 353 / functional group: carboxylic acid

The physiological screening method has the following parameters (which can be changed): stomach: Peff = 0; ASF = 0; pH = 1.30; transit time (hours) = 0.25; volume (mL) = 50; length (cm) = 15.0; (cm)=10.00

Duodenum: Peff=0; ASF=1.305; pH=6.00; transit time (hours)=0.26; volume (mL)=48.25; length (cm)=30.0; radius (cm)=1.60

Jejunal 1: Peff = 0; ASF = 1.366; pH = 6.20; transit time (hours) = 0.95; volume (mL) = 175.3; length (cm) = 62.00; radius (cm) = 1.50

Jejunal 2: Peff = 0; ASF = 1.502; pH = 6.40; transit time (hours) = 0.76; volume (mL) = 139.9; length (cm) = 62.00; radius (cm) = 1.34

Ileum 1: Peff = 0; ASF = 1.675; pH = 6.60; transit time (hours) = 0.59; volume (mL) = 108.5; length (cm) = 62.00; radius (cm) = 1.18

Ileum 2: Peff = 0; ASF = 1.906; pH = 6.90; transit time (hours) = 0.43; volume (mL) = 79.48; length (cm) = 62.00; radius (cm) = 1.01

Ileum 3: Peff = 0; ASF = 2.177; pH = 7.40; transport time (hours) = 0.31; volume (mL) = 56.29; length (cm) = 62.00; radius (cm) = 0.85

Cecal: Peff=0; ASF=0.229; pH=6.40; transit time (hour)=4.50; volume (mL)=52.92; length (cm)=13.75; radius (cm)=3.50

Ascending colon: Peff=0; ASF=0.243; pH=6.80; transit time (hour)=13.50; volume (mL)=56.98; length (cm)=29.02; radius (cm)=2.50

C1-C4: 0.18148/1.0944/0.0734/0.31836

ASF model: Opt logD model

Qh(L/min)=1.5

Percentage of fluid in the small intestine (SI): 40. Percentage of fluid in the colon: 10.

The pharmacokinetic screening method has the following parameters (which can be changed): PK model: compartment

Weight (kg): 82

Blood/plasma concentration ratio: 1

Using experimental plasma Fup (%): 0.75

Kidney clearance rate (L/h): 5.04

Vc (L / kg): 0.15

T 1⁄2(h): 1.69

Gastroplus ^{® is} used to simulate the absorption and pharmacokinetics of reference and test formulations. The in vitro dissolution profile of the ketoprofen hydrochloride formulation was used as an input function to simulate the absorption and pharmacokinetics of the reference (Toprec ^® 25 mg commercial tablet) and the test formulation.

Figure 1 shows the results of in vivo bioavailability of a pharmaceutical composition of the present invention containing Toprec ^® 25 mg commercial lozenge and 25 mg of ketoprofen sodium salt using a model to simulate a post-meal state (Fed state).

The model was used to evaluate the efficacy of the dosage form of the invention. These data show that the dosage form of the invention will be effective. Using the Gastro Plus software, AUC (for a 25 mg ketoprofen sodium soft gel and lozenge formulation, AUC (equal to 1 in the postprandial state and equal to 1 in the Fasted state) and Cmax (meal) The ratio is equal to 1 in the post state and equal to 1.035 in the fast state. The ratio is similar.

The above discussion and description illustrate some embodiments of the invention, but are not intended to limit the implementation of the embodiments.

Figure 1 shows the results of in vivo bioavailability of a pharmaceutical composition of the present invention containing Toprec ^® 25 mg commercial lozenge and 25 mg of ketoprofen sodium salt using a model to simulate a postprandial state.

Claims (11)

A pharmaceutical composition for oral administration comprising: 1% (w/w) to 15% (w/w) of ketoprofen sodium salt; 80% (w/w) to 95% (w/w) one or more liquid hydrophilic carriers; wherein the composition has a pH between 7.5 and 10. The pharmaceutical composition of claim 1, wherein the composition has a pH of 9.5. The pharmaceutical composition of claim 1, wherein the total amount of the liquid hydrophilic carrier is in the range of 85% (w/w) to 95% (w/w). The pharmaceutical composition according to claim 1, wherein the liquid hydrophilic carrier medium is selected from the group consisting of polyethylene glycol, glycerin, propylene glycol, PEG 40 hydrogenated castor oil, polysorbate, and glyceryl cocoate. (glyceryl cocoate), PEG 6 caprylic/caprylic glyceride, poloxamer, labrafil, bismuth hexaethylene glycol glyceride, polyethoxylated castor oil, Glycerol-polyethylene glycoloxystearate or PEG-40 hydrogenated castor oil, ethoxylated fatty alcohol and sorbitan ester. The pharmaceutical composition of claim 1, wherein the liquid hydrophilic carrier medium is polyethylene glycol 600. The pharmaceutical composition of claim 1, wherein the pH is adjusted using citric acid if necessary. The pharmaceutical composition of claim 1, wherein if necessary, the pH is adjusted using potassium hydroxide. The pharmaceutical composition according to any one of claims 1 to 7, wherein the weight ratio of the ketoprofen sodium salt to the liquid hydrophilic carrier is from 1:12 to 1:15. The pharmaceutical composition according to any one of claims 1 to 8, which is in the form of a soft capsule. A method of preparing a pharmaceutical preparation according to any one of claims 1 to 9, comprising the sequential steps of: dissolving the ketoprofen sodium salt in the liquid hydrophilic carrier under stirring to obtain a homogeneous mixture; And then, if necessary, a sufficient amount of alkalizing agent is used to adjust the pH. Use of a composition according to any one of claims 1 to 10 for the preparation of a medicament for the treatment of inflammatory pain.