BRPI0318201B1 - METHOD OF DOSAGE OF NON-STEROID INFLAMMATORY DRUG - Google Patents

Description

(54) Title: NON-STEROID ANTI INFLAMMATORY DRUG FORM (73) Holder: MCNEIL-PPC, INC., North American Society. Address: Grandview Road, Skillman - NJ 08558, UNITED STATES OF AMERICA (US) (72) Inventor: CATHY K. GELOTTE; DOUGLAS R. HOUGH; GERARD P. MCNALLY

Validity Term: 10 (ten) years from 10/02/2018, subject to legal conditions

Issued on: 10/02/2018

Digitally signed by:

Liane Elizabeth Caldeira Lage

Director of Patents, Computer Programs and Topographies of Integrated Circuits

Invention Patent Descriptive Report for FORM OF

DOSAGE OF NON-STEROID ANTIINFLAMMATORY DRUG.

The present invention relates to a new dosage regimen for non-steroidal anti-inflammatory drugs, particularly propionic acids. This dosage regimen provides a sustained therapeutic effect over extended periods of time.

Background of the Invention

Therapeutic agents for the treatment of pain, inflammation and fever include analgesics, anti-inflammatories and antipyretics. Non-steroidal anti-inflammatory drugs (NSAID's) are one type of such therapeutic agents. They include propionic acid derivatives, acetic acid derivatives, phenamic acid derivatives, biphenylcarboxylic acid derivatives, oxicams, and selective NSAIDS for cyclooxygenase-2 (COX-2).

Propionic acids include, for example, ibuprofen, naproxen, and ketoprofen. Ibuprofen, in particular, is a widely used, well-known NSAID having analgesic and antipyretic properties. It has been commercially available as a drug sold without a prescription, in many forms, for several years. Ibuprofen is chemically known as 2- (4-isobutylphenyl) -propionic acid.

NSAIDs are typically administered on a daily basis one to four times, with the daily dose in the range of about 50 to about 2000 milligrams, preferably about 100 to 1600 and most preferably about 200 to about 1200 milligrams.

Acetaminophen is a well-known painkiller, with a daily dose in the range of about 325 to about 4000 milligrams, preferably from about 650 to about 4000 milligrams. Acetaminophen was first used in medicine by Van Mering in 1893, but it was not until 1949 that it gained popularity as an effective alternative to aspirin for painkillers in the non-prescription drug market. The pharmacology of APAP is reviewed by B. Ameer et al., Ann. Int. Med. 87, 202 (1977). Considering the widespread use of APAP and the volume of its manufacture, both its manufacture and its use as an analgesic are well

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known to people skilled in the art.

Administration of NSAIDs, acetaminophen, and other drugs in multiple doses over 12 or 24 hours is known. For example, it is known to administer multiple doses containing equal amounts of ibuprofen over 12 to 24 hours. Continuous-release dosage forms containing ibuprofen are also known.

Palmisano et al., Advances in Therapy, Vol. 5, No. 4, June / August 1988 reports a study of ketoprofen and ibuprofen for the treatment of primary dysmenorrhea. This reference discloses the use of multiple doses of ketoprofen (initial dose of 150 mg followed by subsequent doses of 75 mg) and ibuprofen (initial dose of 800 mg followed by subsequent doses of 400 mg).

It is useful to minimize a patient's drug exposure. In other words, administer the minimum of the total amount of drug that will provide the optimal beneficial therapeutic effect. In particular, it is useful to administer painkillers such as NSAIDs or acetaminophen in a regimen that provides maximum relief with a minimum total dose per day of drug.

Applicants have now found that NSAIDs or acetaminophen provide a mammal, preferably a human, in a specific two-step dosing regimen with an improved therapeutic effect, especially pain relief, compared to known dosing regimens. In particular, an NSAID or acetaminophen is provided to the mammal, either in a single dosage form or in twice-dosage forms, taken separately, in an initial dose followed by a second dose 3 to 5 hours later. It is not necessary to administer additional NSAID or acetaminophen, surprisingly a therapeutic effect of NSAID and acetaminophen is obtained that lasts at least about 6 hours after the administration of the second dose.

Summary of the Invention

The invention provides a method of administering an NSAID, which consists of providing a mammal with an initial dose of said NSAID followed by a second dose of said NSAID about 3 to 5 hours after * ·· · · ·

administration of said initial dose, said NSAID having a duration of therapeutic effect of at least about 6 hours after administration of the second dose.

The invention also provides a method of administering a

NSAID, which comprises providing a mammal with an initial dose of said NSAID followed by a second dose of said NSAID about 3 to 5 hours after administration of said initial dose, without any additional provision of NSAID for at least about 6 hours after administration of said second dose, said NSAID having a duration of therapeutic effect of at least about 6 hours after administration of the second dose.

The invention also provides a method of administering a propionic acid derivative to a mammal over a period of 12 hours, which comprises providing a first plasma peak of said propionic acid derivative of about 25 to about 30 mcg / ml in said mammal about 30 to about 120 minutes after said initial dose, and a second peak plasma concentration of said propionic acid derivative of about 15 to about 30 mcg / ml about 4, 5 to about 5.5 hours after the administration of said initial dose.

The invention also provides a method of administering a propionic acid derivative, which comprises providing a mammal, over a period of 12 hours, with an initial dose of said propionic acid derivative at the beginning of the 12 hour period, followed by a second dose of said propionic acid derivative about 3 to 5 hours after the administration of said initial dose; wherein the starting dose is at least about twice the said second dose, and no further propionic acid derivatives are provided during said 12 hour period.

The invention further provides a dosage form comprising an immediate release portion containing an initial dose of an NSAID and a sudden delayed release portion containing a second dose of said NSAID, said initial dose being at least about twice said second dose.

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The invention also provides a method of administering acetaminophen, which consists of providing a mammal with an initial dose of acetaminophen followed by a second dose of acetaminophen about 3 to 5 hours after administration of said initial dose, said acetaminophen having a duration of therapeutic effect of about 6 hours after administration of said second dose.

The invention also provides a method of administering acetaminophen, which comprises providing a mammal, over a period of 12 hours, with an initial dose of acetaminophen at the beginning of the 12 hour period, followed by a second dose of acetaminophen about 3 5 hours after the administration of said initial dose; wherein the starting dose is at least about twice said second dose, and no further acetaminophen is provided during said 12 hour period.

The invention further provides a dosage form comprising an immediate-release portion containing an initial dose of acetaminophen and a sudden-release portion containing a second dose of acetaminophen, said initial dose being at least about twice said second dose .

The invention also provides a method of administering a therapeutic agent, which consists of providing a mammal with an initial dose of non-steroidal anti-inflammatory drug followed by a second dose of acetaminophen about 3 to 5 hours after the administration of said initial dose of drug non-steroidal anti-inflammatory drug, said non-steroidal anti-inflammatory drug with acetaminophen having a combined duration of therapeutic analgesic effect that lasts about 6 hours after administration of said second dose of acetaminophen.

Brief Description of Drawings

Figure 1 shows ibuprofen absorption levels as a function of time for the various dosing regimens reported in Example 1.

Figure 2 shows pain relief scores versus time for dosing regimens reported in Example 1.

Figure 3 shows the differences in pain intensity (PID) as a function of time for dosing regimes reported in Example 1. Detailed Description of the Invention

In this context, ATDAIRD should mean the average therapeutic duration of action for an effective dose of immediate release of a particular active ingredient. For example, the typical duration of action of an immediate release dose of ibuprofen or ketoprofen is about 4 to about 6 hours. Thus, the ATDAIRD for ibuprofen or ketoprofen is 5 hours. The typical duration of action of an immediate release dose of naproxen is about 8 to about 12 hours. The ATDAIRD for naproxen is therefore 10 hours. The therapeutic duration of action of a particular active ingredient can readily be determined from dosage instructions on the label for immediate release products containing that particular active ingredient.

NSAIDs useful in the present invention include for example 1) NSAIDs derived from propionic acid, 2) NSAIDs derived from acetic acid, 3) NSAIDs derived from phenamic acid, 4) NSAIDs derived from biphenylcarboxylic acid, 5) NSAIDs from oxicam, 6) selective NSAIDs for cyclooxygenase-2 (COX-2), and 7) pharmaceutically acceptable salts of the above compounds.

Examples of acetic acid derivatives are indomethacin, diclofenac, sulindac, tolmetin, and the like. Examples of phenamic acid derivatives are mefenamic acid, meclophenamic acid, flufenamic acid, and the like. Examples of biphenylcarboxylic acid are diflunisal, fluphenisal and the like. Examples of oxycans are piroxicam, sudoxicam, isoxicam, meloxicam, and the like.

In a particularly preferred embodiment, NSAID is selected from derivatives of propionic acid. Propionic acid derivatives are non-steroidal anti-inflammatory drugs / pharmaceutically acceptable analgesics having a free -CH (CH3) COOH or -CH2CH2COOH radical or a pharmaceutically acceptable salt group, such as -CH (CH3) COO-Na + or CH ₂ CH ₂ COO -Na +, which are typically linked directly or through a carbonyl functionality to a ring system, preferably a

aromatic ring system.

Examples of useful propionic acid derivatives include ibuprofen, naproxen, benoxaprofen, naproxen sodium, flurbiprofen, fenoprofen, fenbuprofen, ketoprofen, indoprofen, pyrprofen, carpofen, oxapro5 hay, pranoprofen, microprofen, tioxaprofen, fluoxenprofen, suproprofenprofen, fluoprophenprofen, suproprophenprofen, fluoprophenprofen, fluoprophenprofen, suproprophenprofen, fluoprophenprofen, fluoprophenprofen, and bucclic.

In one embodiment of the invention, the propionic acid derivative is selected from ibuprofen, ketoprofen, flubiprofen, and pharmaceutically acceptable salts and combinations thereof.

Preferably, the propionic acid derivative is ibuprofen, 2- (4-isobutylphenyl) propionic acid, or a pharmaceutically acceptable salt thereof, such as arginine, lysine, or ibuprofen histidine. Other pharmaceutically acceptable salts of ibuprofen are described in US Patent Nos. 4,279,926, 4,873,231, 5,424,075 and 5,510,385, the contents of which are hereby incorporated by reference.

Acetaminophen has the formula N- (4-hydroxyphenyl) acetamide and is sometimes referred to as APAP. The APAP preparation is disclosed in U.S. Patent No. 2,998,450.

According to the invention, the NSAID or acetaminophen is provided to a mammal in need of treatment, in particular pain relief treatment, in a specific dosage regimen for an extended period of time, preferably a period of 12 hours. At time zero an initial dose of NSAID or acetaminophen is provided, ie administered, to the mammal. Approximately 1 ATDAIRD later, a second dose of NSAID or acetaminophen is supplied to the mammal. After the second dose, no more NSAID or acetaminophen is administered for the remainder of the time.

In modalities in which ibuprofen, ketoprofen, or acetaminophen are employed as an active ingredient, the second dose is given to the mammal approximately 3 to 5, preferably about 4, hours after administration of the first dose. In these modalities, no more ibuprofen, ketoprofen, or acetaminophen is administered for the remainder of the 12-hour period.

The starting dose can be, for example, in the range of about 0.10 to about 15 mg / kg, and the second dose can be, for example, in the range of about 0.05 to about 7.5 mg / kg. In one embodiment, the starting dose of NSAID or acetaminophen is at least about twice the second dose of NSAID. In certain embodiments of the invention in which ibuprofen is used, the starting dose is about 400 to about 800 mg, or about 5 to about 12 mg / kg, and the second dose is about 200 to about 400 mg, or from about 2.9 to about 6.0 mg / kg. In a particular embodiment of the invention in which ibuprofen is used, the starting dose is about 400 mg, or about 5.7 mg / kg, and the second dose is about 200 mg, or about 2.9 mg / kg. In certain other modalities in which ketoprofen is used, the starting dose is about 50 to about 100 mg, or about 0.70 to about 1.43 mg / kg, and the second dose is about 25 at about 50 mg, or from about 0.35 to about 0.72 mg / kg. In certain other embodiments in which acetaminophen is used, the starting dose is about 650 to about 1000 mg, or about 9.2 to about 14.3 mg / kg, and the second dose is about 325 at about 500 mg, or from about 4.5 to about 7.2 mg / kg. In addition, the starting dose is within the therapeutic range for the particular active ingredient employed, and is about twice the level of the second dose, which is also in the therapeutic range for the particular active ingredient employed.

The duration of the therapeutic effect of NSAID or acetaminophen is maintained for the extended period of time. In particular, the duration of the therapeutic effect of NSAID or acetaminophen is at least about 1.2 times the ATDAIRD for NSAID after administration of the second dose. In particular modalities where NSAID or acetaminophen has an ATDAIRD of 5 hours, for example, modalities in which the active ingredient is selected from ibuprofen, or ketoprofen, or acetaminophen, the duration of the therapeutic effect is at least about 6 hours after administration of the second dose. Excellent pain relief, in particular, has been found to be maintained for prolonged periods of time, preferably from

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about 12 hours.

In a preferred embodiment of the invention, a propionic acid derivative is administered to a mammal over a 12 hour time period, first providing the mammal with an initial dose of the propionic acid derivative at the beginning of the 12 hour time period, followed by a second dose of the propionic acid derivative about 3 to 5 hours later, the starting dose being at least about twice the second dose. No additional propionic acid derivatives are provided during the 12 hour time period.

In another embodiment of the invention, acetaminophen is administered to a mammal over a period of 12 hours, first providing the mammal with an initial dose of acetaminophen at the beginning of the 12 hour period, followed by a second dose of acetaminophen about 3 5 hours later, the starting dose being at least about twice the second dose. No additional acetaminophen is provided during the 12 hour time period.

In certain embodiments, the invention provides a first peak plasma concentration in the therapeutic range for the particular active ingredient employed at about 0.5 times the ATDAIRD for the active ingredient after administration of the initial dose, and a second peak concentration in the plasma in the therapeutic range for the particular active ingredient employed from about 0.8 to about 1.2 times the ATDAIRD after administration of the initial dose. In one embodiment, the plasma concentration of NSAID or acetaminophen at about 2 times the ATAIRD after administration of the initial dose is below the known therapeutic range for the particular active ingredient employed.

In certain particular embodiments, where the active ingredient has an ATDAIRD of about 5 hours, the invention provides a first peak plasma concentration in the therapeutic range for the particular active ingredient employed about 30 to about 120 minutes after administration of the initial dose, and a second peak of piasma concentration in the therapeutic range for the particular active ingredient employed between about 4 to about 6.5 hours after administration of the initial dose. In one embodiment, the plasma concentration of NSAID or acetaminophen at about 10 hours after administration of the initial dose is below the known therapeutic range for the particular active ingredient employed.

In certain particular embodiments in which ibuprofen is employed, the invention provides a first peak plasma concentration of ibuprofen of about 25 to about 30 mcg / ml in the mammal about 30 to about 120 minutes after administration of the initial dose, and a second peak peak in ibuprofen plasma of about 15 to about 30 mcg / ml about 4.5 to about 5.5 hours after administration of the initial dose. In one embodiment, the plasma concentration of ibuprofen at about 10 hours after administration of the starting dose is less than about 10 mcg / ml. In another embodiment, the plasma concentration of ibuprofen at about 6 hours after the second dose is less than about 10 mcg / ml.

NSAID or acetaminophen can be administered in various dosage forms, for example, solid dosage forms such as tablets, capsules, liquid dosage forms such as syrups and suspensions. NSAID or acetaminophen can also be administered transdermally, or parenterally, as intravenously, intramuscularly, or subcutaneously. NSAID or acetaminophen can also be administered rectally, for example, as a suppository.

The starting dose and the second dose can be administered together or separately. For example, if administered separately, the starting dose can be administered in a first immediate release dosage form, and the second dose can be administered about 3 to 5 hours later in a second immediate release dosage form.

In one embodiment, the starting dose and the second dose are administered in a single dosage form, preferably a single solid dosage form. For example, such a dosage form may comprise a single dosage form composed of an immediate release portion containing the initial dose of NSAID or acetaminophen and a sudden delayed release portion containing the second dose of NSAID or ace10 • * ··· · · ··· »· ··· * ··· · · taminophen. Such a single solid dosage form can be a multilayer tablet, a multiparticulate tablet or the like. It can optionally include a barrier layer between the two portions, for example, a polymeric barrier.

In this context, a sudden release profile ”refers to a release profile that meets immediate release criteria during a specified interval. The specified interval can optionally follow a predetermined delay time. By delayed sudden release profile is meant that the release of at least a portion or dose of that particular active ingredient of the dosage form is delayed for a predetermined time after contact with a liquid medium, such as after ingestion by the patient, and the period of delay is followed by ready (ie immediate) release of that dose of active ingredient.

In modalities in which the initial dose and second dose are provided by a dosage form that provides a delayed sudden release profile, the dissolution of the sudden release portion of the active ingredient, after the delay period, meets the USP specifications for immediate release containing the active ingredient. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP 2 apparatus (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the dosage form is released from it in 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP 2 apparatus (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the dosage form is released from the even within 60 minutes of dosing. (See USP 24, version 2000, 19 - 20 and 856 (1999)).

The following examples further illustrate the invention, but are not to limit the invention in any way.

Example 1

A single-blind, randomized, parallel, placebo-controlled, PK / PD study of toothache, was conducted during a 12-hour observation period to assess pharmacokinetic profiles, • · · · ♦ ·· · · ·· · ·· «pharmacodynamic, efficacy and safety of certain ibuprofen dosing regimens. Specifically, ibuprofen 600 mg single-dose prolonged-release capsules were compared with equivalent total doses of 200 mg immediate-release capsules administered in three different dosage regimens, as well as placebo, in the treatment of postoperative toothache. moderate to severe.

Ibuprofen was administered as 600 mg prolonged-release capsules or one or more 200 mg immediate-release ibuprofen capsules.

The patients evaluated in this study consisted of non-pregnant and non-breastfeeding male or female volunteers, 16 years of age or older, who complained of moderate to severe pain after surgical extraction of three or four third molars with at least one third mandibular molar partially or completely impacted on the bone. The impacted term included: partial bone impaction, bone impaction, or complicated bone impaction. A total of 210 patients participated in the study. 208 patients were eligible for efficacy analyzes.

All patients who met the participation criteria were enrolled in one of the two study subgroups. A subgroup of patients was evaluated in both pharmacokinetic and pharmacodynamic modality (PK group). The other subgroup of patients had only analgesic efficacy assessments (non-PK group). A separate randomization program was used for each of the two subgroups. Patients from both subgroups were randomly assigned to one of the following five treatments:

Prolonged release of Ibuprofen Single dose of 600 mg at 0 hour Immediate release of Ibuprofen Single dose of 600 mg at 0 hour Immediate release of Ibuprofen 400 mg at 0 hour; 200 mg at 4 hours Immediate release of Ibuprofen 200 mg at 0, 4, and 8 hours Placebo

Patient assessments for pain intensity and relief, as well as blood samples for plasma ibuprofen analysis were

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obtained at the study site at hours 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 4.5, 5, 6, 7, 8, 8.5, 9 , 10, 11 and 12. A stopwatch technique was used to measure the onset of significant pain relief.

Figure 1 shows the blood levels of ibuprofen obtained with the four non-placebo treatments as a function of time over a 12-hour study period. Figure 2 indicates pain relief scores as a function of time for the five treatments including placebo. Surprisingly, the 400/200/0 administration of ibuprofen according to the invention provided excellent pain relief throughout the 12 hour study period. During the first four hours, treatment 400/200/0, along with treatment immediate release 600/0/0, provided superior pain relief over other treatments. During the 4 to 12 hour interval, treatment 400/200/0 alone provided the highest scores for pain relief, despite the fact that no additional ibuprofen was administered after the first four hours.

Similarly, figure 3 shows the differences in pain intensity (PID) reported as a function of time for all five treatments. Again, the 400/200/0 treatment according to the invention provided the best PID during the 12 hour study period, particularly after the four hour mark, when the PIDs reported for other treatments decreased. It is surprising that the treatment according to the invention did not include additional administration of ibuprofen after the four hour mark.

Example 2

A dosage form according to the invention is prepared as follows. The dosage form is an immediate release / delayed release combination capsule containing 200mg and 10Omg of ibuprofen, respectively. The immediate-release portion is in the form of granules, while the delayed-release portion is in the form of a compression-coated core.

Step A

First, a granulation of ibuprofen is prepared from the following ingredients:

Ingredient Business name- ciai Manufacturer ma / comori wet Ibuprofen powder Albemarle Corp. Orangeburg, SC 100 Micro-cellulose crystalline Avicel pH 101 FMC Corp. Newark, DE 19711 5.4 Pregelatinized starch National 1551 National Starch & Chem. Co. Bridgewater, NJ 2.2 Stearate Magnesium Mallinckrodt Inc., St. Louis, Missouri 1.1 Total 108.7

The ibuprofen powder, AVICEL pH 101 and pregelatinized starch are mixed in a 4.75 l (5qt) bowl of an electric mixer (Hobart Corp., Dayton, OH). Water is added to the powder mixture while mixing at low speed. The mixing process continues for 10 minutes. The granulated product is removed from the bowl and dried at room temperature for 12 to 16 hours to remove all residual solvent. The granules are sieved through a No. 20 mesh sieve and placed in a 1.9 I (2 qt) P-K P-K mixer. Magnesium stearate is added to the dry granules, followed by mixing for another 5 minutes.

Step B

The granulated product from Step A is compressed into cores in a Beta press (Manesty, Liverpool, UK). The press is equipped with 6 mm diameter concave and round punch and die units. The granulated product is fed into the press die cavity and pressed into solid cores using an operating pressure of 103.5 bar (1500 lb / in ² ). The compressed cores weigh 109 mg and contain 100 mg of ibuprofen. Step C

An ethyl cellulose powder is prepared as a compression coating for the sustained sustained release portion of the dosage form. The following ingredients are used:

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Inarediente Manufacturer mq / tablet Ethyl cellulose powder (grade N-10-F) Shin-Etsu Chem. Ind. Co. Ltd. Tokyo, Japan 304.6 Magnesium stearate Mallinckrodt inc., St. Louís, Missourí 1.4 Total 306

Ethyl cellulose powder and magnesium stearate are put into

a 1.9 I (2-quart) P-K mixer and mixed for 5 minutes.

Step D

Compression-coated cores are prepared using a Carver Model M laboratory hydraulic press (Fred S. Carver, Inc., Hydraulic Equipment, Summit, NJ). The press is equipped with 9 mm round concave punch and die units. Each core is prepared by adding 153 mg of Step C ethyl cellulose powder in a matrix, and manually placing a Step B core in the center of the powder. The remaining 153 mg of ethyl cellulose powder is then poured into the matrix, which is then compressed at 207 bar (3000 lb / in ² ) operating pressure to prepare the compression-coated core. The compression-coated cores weigh 415 mg and contain 100 mg ibuprofen.

Step E

The finished dosage form comprising immediate-release and abruptly-delayed ibuprofen portions is prepared as follows. 218 mg of ibuprofen granulation from Step A is added in the first half of a capsule (DB Caps, size AA, Capsugel, Morris Plains, NJ). Then, a compression-coated core from Step D is placed manually in the capsule. The second half of the capsule is then inserted into the first half of the capsule. The finished dosage form contains 218 mg of granulation of ibuprofen (equivalent to 200 mg of ibuprofen) as the immediate release portion of ibuprofen and a 415 mg compression-coated ibuprofen core (equivalent to 100 mg of ibuprofen) as the dose of sudden delayed release of ibuprofen.

Example 3

A dosage form according to the invention is prepared as follows. The dosage form is a combined capsule for immediate release / sudden release delayed containing 200 mg and 100 mg of ibu5 profene, respectively. The immediate release portion is in the form of granules, while the delayed sudden release portion is in the form of an atomized coated core.

Step A

A granulation of ibuprofen for the immediate release portion is prepared as in Example 2 above.

Step B

The granulation from Step A is compressed into cores as in Example 2 above.

Step C

A coating dispersion for the sustained sustained release portion of the dosage form is prepared using the following ingredients:

Coating Business name- ciai Manufacturer mq / comori wet Hydroxypropyl methylcellulose Methocel K4M The Dow Chemical Company, Midland, Michigan 48674 20.8 Baby powder Charles B. Chrystal Co. New York, NY 8.3 Povidona Koilidon K-30 BASF Corp. Parsipany, NJ 10.4 Polyethylene Glycol 400 Union Carbide Corporation, Danbury, CT 06817 4.1 Ethanol (dried as solvent) Water (dry as solvent) Total 43.6

The coating dispersion is prepared by adding hydroxypropyl methylcellulose, talc, povidone, and polyethylene glycol 400 to a suitable ethanol / water mixture (94% / 4%) to produce a polymeric dispersion at

10.5%. The dispersion is left at room temperature for 12 hours.

Step D

Atomized coated ibuprofen cores are prepared as follows. The Step B cores are placed in a 24 Acella coating pan (Manesty, Liverpool, UK) and agitated by air with the Step C coating dispersion until the cores are evenly coated. The coated cores are dried in an oven at 50 ° C for 24 hours to evaporate the solvent. The coated cores weigh 153 mg and contain 100 mg of ibuprofen.

Step E

The finished dosage form comprising portions of immediate release and delayed release of ibuprofen is prepared as follows. 218 mg of ibuprofen granulation from Step A is added in the first half of a capsule (DB Caps, size AA, Capsugel, Morris Plains, NJ). A spray coated ibuprofen core from Step D is placed manually in the capsule. The second half of the capsule is then inserted into the first half to provide the finished dosage form. The finished dosage form contains 218 mg of ibuprofen granulation (equivalent to 200 mg of ibuprofen) as the immediate release portion of ibuprofen and a spray-coated ibuprofen core of 153 mg (equivalent to 100 mg of ibuprofen) as the dose sudden release of ibuprofen.

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Claims (3)

1. Dosage form, characterized by the fact that it comprises an immediate release portion containing an initial dose of ibuprofen and a sudden delayed release portion containing a second dose of ibuprofen that releases 3 to 5 hours after the initial dose, the said initial dose twice said second dose; and the time for the dissolution of the delayed sudden release portion, after the delay period, meets the specifications of the American Pharmacopoeia (USP 24) for immediate release tablets containing non-steroidal anti-inflammatory drugs. Dosage form according to claim 1, characterized in that said dosage form is a solid dosage form. Dosage form according to claim 1, characterized by the fact that the initial dose is 5 to 12 mg / kg and said second dose is 2.9 to 6 mg / kg. Petition 870180036593, of 05/04/2018, p. 5/8 Pharmacokinetic data (| ω / βοω) ouojojdnqi 2/3