Oral dosage form providing fast absorption of drug

Our pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government. Email:marketing@medicilon.com.cn Web:www.medicilon.com

Oral dosacie form providing fast absorption of druci The present invention relates to oral administration of the drug diclofenac which has been widely used as, inter alia, an anti-inflammatory agent or for the treatment of pain.

For the treatment of pain, an obvious goal is to have a rapid onset of action for an as early a relief as possible of the patient. It is accepted that onset of action is directly related to rate of absorption.

In the art, the rate of absorption is usually described by the use of the pharmacokinetic parameters "time to peak plasma concentration" (tmax) and "peak plasma concentration"

(Cmax)= However, these parameters are limited in their ability to assess rate of absorption and the Federal Drug Administration in the USA have introduced a new criterion to be used to assess early exposure. An early exposure measure may be indicative of the clinical onset of action. This is called the AUC,maxref which is defined as the area under the pharmacokinetic curve (AUC) until the median tmax for the reference formulation. This measure of early systemic exposure, together with peak exposure (Cmax) will better assess the rate and extent of absorption.

It is further known that the fundamental processes controlling drug absorption are drug dissolution and gastrointestinal permeability. As a consequence it is also known that the physicochemical characteristics of the drug and/or the dosage form can affect the rate of absorption and therefore onset of action. For drugs which have low solubilities and dissolution rates such as ibuprofen and diclofenac - classified as so-called Class II

compounds according to the "Biopharmaceutics Classification System" - it is known that the rate of absorption is limited by the dissolution rate of the drug. It is very well known in the art that for drugs with poor solubility and dissolution rates the use of a salt form of the drug acts to buffer the solution and modify the microenvironment which act to increase the solubility and dissolution rate respectively, leading to an increased absorption rate.

Relevant examples from the art include pharmacokinetic studies where it was demonstrated that an ibuprofen salt - ibuprofen lysinate - is more rapidly absorbed than ibuprofen administered as the free acid.

Example 1: Composition of 12.5 mg Diclofenac potassium soft gelatin capsule Composition of the capsule fill contents:

Name of ingredients Quantities (mg /capsule) Drug substance Diclofenac potassium 12.50 Other ingredients Macrogol 600 (= Polyethylene glycol 600) 100.00 Glycerol 85% 6.25 Purified water 6.25 Composition of the capsule shell:

Name of ingredients Quantities (mg/capsule) Gelatin 51.34 Glycerol 85% 14.93 Sorbitol liquid, partially dehydrogenated 10.86 (e.g. Polysorb 85/70/00) Quinoline yellow 70% (= E104) 0.0060 Example 2: Composition of 25.0 mg Diclofenac potassium soft gelatin capsule Composition of the capsule fill contents:

Name of ingredients Quantities (mg /capsule) Druci substance Diclofenac potassium 25.0 Other inciredients Macrogol 600 (= Polyethylene glycol 600) 200.00 Glycerol 85% 12.50 Purified water 12.50 Composition of the capsule shell:

Name of ingredients Quantities (mg /capsule) Gelatin 89.85 Glycerol 85% 26.12 Sorbitol liquid, partially dehydrogenated 19.00 (e.g. Polysorb 85/70/00) Quinoline yellow 70% (= E104) 0.011 The beneficial properties due to oral administration of diclofenac soft gelatin capsules can be seen e.g. from the following tests:

(1) Comparative bioavailability study: Comparison of two 12.5 mg diclofenac potassium tablets with two 12.5 mg diclofenac potassium soft gelatin capsules The following products were compared in a two way cross over single dose pharmacokinetic study using 42 fasted healthy human volunteers:

Test formula A: soft gelatin capsules from example 1 Test formula B: commercially available swallow tablets containing diclofenac potassium 12.5mg Each volunteer swallowed two samples of one of the formulations equivalent to 25mg of diclofenac potassium, followed by 240 mL of water on two separate occasions at least 14 days apart. Blood samples were taken pre-dose and at 15 min, 25 min, 35 min, 45 min, 1.0 h, 1.25 h, 1.5 h, 1.75 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 6.0 h, 8.0 h, and 10 hours post dose.

Serum diclofenac potassium levels were determined by a fully validated LC/MS-MS method and diclofenac potassium plasma levels vs time plots were plotted for each volunteer. The mean AUCtmaxref for formulation A was 294 ng x hour/mL vs 158 ng x hour/mL for formulation B.

Mean plasma concentration of diclofenac (ng/mL) Time Soft gelatin Tablet capsule Pre-dose 0.0 0.0 15 min 385 261 25 min 915 439 35 min 764 384 45 min 477 321 1 h 256 226 1.25 h 177 179 1.5 h 134 159 1.75 h 103 137 2 h 74 108 2.5 h 52 97 3 h 38 93 3.5 h 27 64 4 h 21 41 6 h 8 10 8h 4 4 h Not estimable 2 (2) Comparative bioavailability study: Comparison of two 12.5 mg diclofenac potassium tablets with one 25 mg diclofenac potassium soft gelatin capsule The 25mg Diclofenac potassium soft gelatin capsule was tested in a pharmacokinetic study using a similar design as detailed under (1) for the 12.5mg Diclofenac potassium soft gelatin capsule, except that the soft gelatin capsule was administered as one 25mg dosage form instead of two 12.5mg ones. The ultrafast absorption rate for the 25mg soft gelatin capsule was observed, when compared to two 12.5mg tablets.

(3) Clinical study in 3rd molar extraction: Double-blind, double-dummy, placebo-controlled, parallel-group, randomized trial of diclofenac potassium soft gelatin capsule (12.5 mg) vs paracetamol (500 mg) tablets and placebo in patients with moderate or severe pain within 8 hours of extraction of impacted third molars. All are treated with an initial dose of 2 soft gelatin capsules or 2X 500 mg of paracetamol tablets or placebo followed by 1 or 2 capsules or tablets, as needed, every 4 to 6 hours, up to a maximum of 6 of each type.

Efficacy in control of acute pain is determined at baseline, and then at 20 minutes, 40 minutes, 1, 2, 3, 4, 5, and 6 hours after dosing. Significantly higher levels of analgesia are observed in the soft gelatin capsule group at 20 minutes, 40 minutes and 1 hour after the initial dose, compared to paracetamol group.