WO2009157010A1

WO2009157010A1 - An intravenous drug delivery system

Info

Publication number: WO2009157010A1
Application number: PCT/IN2008/000754
Authority: WO
Inventors: Hari Ram Goel
Original assignee: AKUMS DRUGS AND PHARMACEUTICALS Ltd
Current assignee: AKUMS DRUGS AND PHARMACEUTICALS Ltd
Priority date: 2008-06-25
Filing date: 2008-11-05
Publication date: 2009-12-30
Anticipated expiration: 2010-12-25

Abstract

The present invention is related to administer Paracetamol & Diclofenac Sodium through Intra venous route through an aqueous vehicle. The Paracetamol & Diclofenac Sodium is dissolved in Water for Injection with the help of Passive Ingredients responsible for Buffers, Isotonic, etc. The process is done at different temperatures. The activity pf Paracetamol & Diclofenac Sodium increases after dissolution in aqueous form & make the patient more comfortable.

Description

COMPLETE SPECIFiCATION

TITLE OF INVENTION: "AN INTRAVENOUS DRUG DELIVERY SYSTEM"

Field of Invention;

Filed of invention is related to the drug delivery system. More particularly field is related to the pharamaceuical and diclofenac sodium forumaltion for the intravenous administration of a drug, Most particularly invention is related a pharmaceutical composition for intravenous administration containing paracetamol and diclofenac sodium in an aqueous base.

Background of the invention;

In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body. Obviously, a substance must be transported from the site of entry to the part, of the body where its action is desired to take place (even if this only means penetration through the into the skin). However, using the body's transport mechanisms for this purpose can be far from trivial, The pharmacokinetics properties of a drug (that is, those related to processes of uptake, distribution, and elimination) are critically influenced by the route of administration.

Routes of administration can broadly be divided into;

• topical: local effect, substance is applied directly where its action is desired enteral: desired effect is systemic (non-local), substance is given via the digestive route, parenteral: desired effect is systemic, substance is given by other routes than the digestive tract

Parenteral by injection;

• intravenous (into a vein), e.g. many drugs,

• intraarterial (into an artery), e.g. vasoioditor drugs in the treatment of vasospam and therobylotic drugs for treatment of embolisim,

• intramuscular (into muscle), e.g. many vaccines , antibiotics, and long- term psychoactive agents

• intracardiac (into the heart), e (jnσ longer commonly performed)

• ^■ subcutaneous (under the skin), e.g. insulin

• intraosseous infusion (into the bone marrow) is, in effect, an indirect intravenous access because the bone marrow drains directly into the venous system. This route is occasionally used for drugs and fluids in emergency medicine and paediatrics when intravenous access is difficult.

• intradermal (into the skin itself) is used for skin testing some allergens and also for tattoos

• intrathecal (into the spinal canal) is most commonly used for spinal anesthesia and chemotherapy

Paracetamol or acetaminophen is a widely-used analgesic and antipyretic, unlike aspirin it is not a very effective anti-inflammatory agent. It is well tolerated, lacks many of the side-effects of aspirin and is available over-the-counter so it is commonly used for the relief of fever headaches, and other minor aches and pains. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of additional non-steroidal anti-inflammatory drugs (NSAIDs) to be used, and thereby minimizing overall side-effects. It is also used in combination with opioid analgesics It is a major ingredient in numerous cold and flu medicationsintraperitoneai (infusion or injection into the peritoneum) e.g. peritoneal dialysis.

Diclofenac with various drug dose combinations is a non-steroidal antiinflammatory drug (NSAiD) taken ϊo reduce inflammation and as an analgesic reducing pain in conditions sucrvas arthritis or acute injury It can also be used to reduce menstrua!. The name is derived from its chemical name: 2-(2,6- dichloranilino) phenylacetic acid Diclofenac may also be a unique member of the NSAIDs.There is some evidence that diclofenac inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes {also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit phospholipase A₂ as part of its mechanism of action. These additional actions may explain the high potency of diclofenac - it is the most potent NSAiD on a broaό basis.

There are different types of drug delivery modes are available for the nonsteroidal anti-inflammatory drugs (NSAlDs) like paracetamoi. Both patent and non patent literature survey reveals,

WO96/14839 PCT Pub. Date May 23, 1996A pharmaceutical composition for oral administration for the treatment of acute pain and inflammation comprises an inclusion complex of a non-steroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof and a cyclodextrin, and a physiologically acceptable alkali agent selected from the group consisting of alkali and alkaline earth metal carbonates, bicarbonates, phosphates and hydroxides, and water soluble amines, in an amount equivalent to between 2 and 30 molar equivalents inclusive of the non-steroidal anti-inflammatory drug, the alkali agent being capable of forming an alkaline diffusion layer around the composition in the grastrointestinal tract.

United States Patent 6,028,222 discloses a combination liquid paracetamol combination. Novel stable paracetamoi compositions for use in therapeutic chemistry and specifically galenic pharmacy are disclosed. The compositions contain a solution of paracetamol in an aqueous solvent combined with a buffer having a pH of 4 to 8, and a frfee radical capturing agent. A water-insoluble inert gas is carefully bubbled through the aqueous solvent to remove oxygen from the medium. Said compositions may also be combined with a centrally or peripherally acting analgesic agent, and are provided as inject able compositions for relieving pain.

Object of the invention;

An object of the invention is to design a direct injection method for the paracetamol and diclofenac sodium. Another object of the invention is to formulate intravenous formulation of the paracetamol and diclofenac sodium in combination. Yet another object of the invention is to prepare water based formulation of intravenous administration of the paracetamol and diclofenac sodium.

Summary of the invention;

Present invention is related to intravenous administration of the paracetamol and disclofeπac sodium in combination, in this method paracetamol powder and diclofenac sodium are dissolved separately in the aqueous phase and suitable pH is adjusted by acid or base and this solution is directly administrated in the patients body though the direct injection.

The advantages of the direct delivery of the combination in to blood flow and immediate relief form the suffering.

Detailed Description of the invention;

The subject in the methods described herein can be, e.g., a mammal, e.g., a human, mouse, rat, dog, cat, horse, cow, pig, or non-human primate. In some embodiments, the subject is a juvenile human, e.g., a subject less than 7 years of age.

The term "pharmacologically effective amount" as used herein means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.

Administration to the subject in the methods described herein can be, e.g., intravenous, intramuscular, subcutaneous, sublingual, oral, rectal or via aerosol delivery. The compositions are preferably suitable for internal use and include an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers! The compounds are especially useful in that they have very low, if any, toxicity.

The method of administration of the paracetamol and diclofenac sodium in the present invention is through the intravenous route through an aqueous vehicle. The paracetamol is dissolved in water for injection. The injection thus prepared also contains adjuvants, buffers isotonic.

Adjuvants are pharmacological or immunological agents that modify the effect of other agents (e.g., drugs, vaccines) while having few if any direct effects when given by themselves. In this sense, they are roughly analogous to chemical,

Chemically, Sodium sulfite (sodium sulphite) is a soluble compound of sodium It has a moJecuiar weight of 126.04.. \t is also used as a presser to prevent dried fruit from discoloring, and for preserving meats, and is used in the same way as sodium thiosulfate to convert elemental halides to their respective acids

Phosphate buffered saline (abbreviated PBS) is a buffer solution commonly used in biochemistry and other branches of biological research. It is a salty solution containing sodium chloride and (in some formulations) sodium chloride and potassium dihydrogen phospahte . The buffer helps to maintain a constant pH The osmolarity and ion cone Potassium hydrogen phthalate, often called simply KHP, is a white or colorless, ionic soiid that is the monopotasssum salt of phthalic acid. The hydrogen is slightly acidic, and it is often used as a primary standard for acid-base titrations because it is solid and air-stable, making it easy to weigh accurately. It is, however, slightly hygroscopic and is generally kept in a desiccator before use. It is also used as a primary standard for calibrating pH meters because, besides the properties just mentioned, its pH in solution is very stable.

KHP can be used as a buffering agent (in combination with HCI or NaOH depending on which side of pH 4.0 the buffer is to be) but should not be used as a buffer for decarboxylation reactions, as these will degrade the KHP and mop up the conjugation groups

Stability of the aqueous solutions mentioned above does not solely depend on the choice of a given earner, ϊt also depends on other variables, such as careful adjustment of pH, removal of oxygen dissolved in the carrier and addition of a free radical antagonist or a free radical scavenger.

Removal of dissolved oxygen is readily accomplished by bubbling an inert gas and preferably by bubbling nitrogen.

The appropriate free radical antagonist is chosen among the derivatives of ascorbic acid, those derivatives bearing at least a thiol functional group and straight chain or . cyclic polyhydric compounds.

Preferred ascorbic acid derivatives are D- or L-ascorbic acid, an alkali metal ascorbate, an alkaline earth metal ascorbate or even still an aqueous medium- soluble ascorbic acid ester.

Free radical scavengers, bearing a thiol functional group may be an organic compound substituted by one or more thiol functional groups, of the aliphatic series such as cystein, acetylcy stein, thioglycollic acid and salts thereof, thiolactic acid and salts thereof, dithlothrβltol, reduced glutathion, thiourea, thioglycerol, methionine and mercaptoethane sulfonic acid,

The polyol used as a free radical scavenger is preferably a straight chain or a cyclic, polyhydroxy alcohol such as mannitol, sorbitol, inositol, isosorbide, glycerol, glucose and propylene-glycols.

Among free radical scavengers required pour stabilizing paracetamol, the ascorbic acid derivative currently preferred is sodium ascorbate. Preferred thiol functional group substituted derivatives are cystein, reduced-slate glutathion, N- acetylcystein and mercaptoethane sulfonic acid.

It may appear as convenient to combine several free radical scavengers as far as they are water-soluble and mutually compatible. Especially convenient free radical scavengers are mannitol, glucose, sorbitol or even glycerol. These may be readily combined.

It may appear as convenient to add to the preparation one or a number of complexing agents to improve stability of the molecule since the active ingredient is sensitive to the presence of trace metafs that eventually speed up its decay. Sodium chloride, also known as common salt, table salt, or halite is a chemical compound with the formula Sodium chloride is the salt most responsible for the salinity.

The gas that is bubbled into the solution to drive out oxygen, may be nitrogen or carbon dioxide or still an inert gas. Nitrogen is favoured.

lsotonicity of the preparation may be achieved by adding an appropriate quantity of sodium chloride, glucose, Sevulose or postassium chloride, or calcium chloride, or calcium gluconoglucoheptonate, or mixtures thereof. The preferred isotonizing agent is sodium chloride. The buffer used is a buffer compatible with parenteral administration in humans, the pH of which roay be adjusted between 4 and 8. Preferred buffers are based on alkali metal alkaline earth metal acetates or phosphates. A more preferred buffer is sodium acetate/hydrogene phosphate adjusted to the required pH with hydrochloric acid or sodium hydroxide. The concentration of such a buffer may be comprised between 0.1 and 10 mg/ml. The preferred concentration is confined in the range of 0.25 to 5 mg/ml.

On the other hand, preparations for injection have to be sterile and should lend themselves to heat treatment sterilization, it is known that in certain conditions, antioxidants such as glutathion are broken down JFIALAIRC A. et al., J. Pharm. Biomed. Anal., vol. 10, No 6, pp. 457-460 (1992)]. The breakdown of reduced giutathion during heat treatment sterilization ranges from 40 to 77% depending on the selected temperature conditions. During such sterilization procedures, it is convenient to employ means capable of preserving the integrity of these antioxidants. Addition of complexing agents to aqueous solutions inhibits thermal decomposition of thiol derivatives, such as glutathion, edentate sodium.

Liquid pharmaceutical compositions according to the invention are preferably compositions intended for injection. The paracetamol content of the solution may range from 2 mg/ml to 50 mg/ml in case of so calied dilute solutions, i.e. that can be directly infused by intravenous route and from 60 mg/ml to 350 mg/ml where so-called concentrated solution are considered, i.e. either intended for direct injection by intravenous or intramuscular route, or intended to be diluted prior to slow infusion administration. The preferred concentration are comprised between 5 and 20 mg/ml for dilute solutions and between 100 and 250 mg/ml for concentrated solutions or mostly the amount which is pharmaceutically effective amount is used for ihe preparation of the said formulation.

Pharmaceutical compositions according to the invention may further contain another active ingredient that enhances the specific effect of paracetamol.

In particular, the pharmaceutical compositions according to the invention diclofenac such as for exampie a diclofenac sodium

The term isotonic may refer to;

• Isotonic, muscle exercise

. isotonic (exercise physiology) for the term associated with muscle contraction

• solutions that have equal osmotic pressure, such as the isotonic environment in cell biology

• to assist athletes rehydrate while balancing electrolytes

Concentration of the solution usually match those of the human body (isotonic). The process is earned at the different temperatures. The activity increases after the direct administration of the paracetamol and patient gains immediate relief.

Method followed for the preparation of the combination formulation is dissolving paracetamol and Diclofenac sodium separately in water. Foolowed by an addition of the dosodium edetate and sodium chloride. pH of the mixture mixture is adjusted to 6.5-7.2 by using acid-base combination. Here in the present invention this is HQ-NaOH. The desired volume is achived by using degassed and sterlized water.

Examples

paracetamol 50-500 mg Diclofenac sodium 10-50 mg Sodium hydrogen 0.0025 g 0.00025 g 000025 g phosphate dihydraie Sodium chloride 0.002 g 0.002 g 0002 g Disodiυm ethylene 0.0001 g 0.0001 g 0.0001 g Hydrochloric acid or q.s. pH 7.0 q.s. pH 7.5 q.s Sodium hydroxide

Water for injection q.s.f. 1000 ml q.s.f. 1000 ml q.s.f. 1000 ml Nitrogen q.s.f. bubbling q.s.f

Claims

I/We Claims:

1. An intravenous drug delivery system comprising;

(a) water;

(b) pharmaceutically acceptable adjuvants, excipients, chelating agents,

(c) isotonic solution /buffer solution,

(d) pharmaceutically effective amount of active ingredients wherein, water used for the said system is purged with nitrogen gas.

2. An intravenous drug delivery system according to claim 1 wherein water is 1.0-1000 ml.

3. An intravenous drug delivery system according to claim 1 wherein pharmaceutically acceptable chelating agent is disodium edetate.

4. An intravenous drug delivery system according to claim 1 wherein isotonic solution /buffer solution is phosphate buffer , sodium phosphate dibasic anhyrdous, sodium chloride, sodium suSphiate as an preservative.

5. An intravenous drug delivery system according to claim 1 wherein active ingridents are paracetamol and diclofenac sodium.

6. A method for preparation of intravenous drug delivery system comprising;

(a) purging nitrogen gas through water ;

(b) dissolving pharmaceutically effective amount of the paracetamol and diclofenac sodium separately,

(c) addition of appropriate amount of sodium phospahte dibasic anhydrous, sodium chloride, sodium suiphaite, complxeing agent disodium edetate,

(d) adjusting pH 7.0-7.5 by using acid or base;

(e) making up volume with the degassed water.

7. An intravenous drug delivery system as described with reference to description and example herein.

8. Signature: __. \ ,. _v .. f\ - f Λ

Applicant: AKUMS DRUGS & PHARMACEUTICALS LTD.