COMPLETE SPECIFICATION
APPLICANT: AKUMS DRUGS & PHARMACEUTICALS LTD.
ADDRESS: 304, MOHAN PLACE,
LOCAL SHOPING COMPLEX, ABOVE STATE BANK OF INDIA,
BLOCK-C, SARAWATI VIHAR,
DELHI-110034, INDIA.
TITLE OF INVENTION: "AN INTRAVENOUS DRUG DELIVERY SYSTEM"
Field of Invention;
Filed of invention is related to the drug delivary system. More particulalry field is related to the pharamaceuical and diclofenac sodium forumaltion for the intravenous administration of a drug. Most particlaurly invention is related a pharameceutical composition for intravenous administartion containing paracetamol and diclofenac sodium in an aqueous base.
Background of the invention;
In pharamacology 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;
• intravemous (into a vein), e.g. many drugs,
• intraarterial (into an artery), e.g. vasoloditor 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 (no 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, thereby minimizing overall side-effects. It is also used in combination with opioid analgesics It is a major ingredient in numerous cold and flu medicationsintraperitoneal (infusion or injection into the peritoneum) e.g. peritoneal dialysis.
Diclofenac with various drug dose combinations is a non-steroidal antiinflammatory drug (NSAID) taken to reduce inflammationand as an analgesicreducing pain in conditions such as arthritis or acute injury It can also be used to reduce menstrual. 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 broad basis.
There are different types of drug delivery modes are availbe for the non-steroidal anti-inflammatory drugs (NSAIDs) like paracetamol. Both patent and non patent litreture survey reveals,
W096/14839 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 paracetamol 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 free 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 injectable compositions for relieving pain.
Object of the invention;
An object of the invetion is to design a direct injection method for the paracetamol and diclofenac sodium. Another object of the invention is to formulate intraveous formulation of the paracetamol and diclofenac sodium in comibation. Yet another object of the invention is to prepare water based formulation of intravenous adminstration of the paracetamol and diclofenac sodium.
Summary of the invention;
Present invention is related to intravenous administration of the paracetamol and disclofenac sodium in combination. In this method paracetamol powder and diclofenac sodium are dissolved seperatly in the aquesous phase and suitable pH is adjusted by acid or base and this solution is direcly adminstated in the patients body though the direct injection.
The advantages of the direct delivary of the combination in to blood flow and immediate relief form the suffering.
Detailed Descripation 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 immunologicalagents 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 molecular weight of 126.04.. It is also used as a preser 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 solid that is the monopotassium 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 carrier. It 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, acetylcystein, thioglycollic acid and salts thereof, thiolactic acid and salts thereof, dithlothreltol, 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 metals 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.
Isotonicity of the preparation may be achieved by adding an appropriate quantity of sodium chloride, glucose, levulose 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 may be adjusted between 4 and 8. Preferred buffers are based on alkali metal alkaline earth metai 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 betwenn 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 glutathion 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 called 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 the 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 example 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 carried 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 seperatly in water. Foolowed by an addtion 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 HCI-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 dihydrate Sodium chloride 0.002 g 0.002 g 0002 g Disodium 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

I/We Claims:
1. An intravenous drug delivary system comprising;
(a) water;
(b) pharamaceitically aceptable adjuvants, excipients.chelating agents,
(c) isotonic soution /buffer solution,
(d) pharmaceitically effectve amount of active ingridents, wherein, water used for the said system is purged with nitrogen gas.

2. An intravenous drug delivary system accodring to claim 1 wherein water is 1.0-1000 ml.
3. An intravenous drug delivary system accodring to claim 1 wherein pharamaceitically aceptable chelating agent is disodium edetate.
4. An intravenous drug delivary system accodring to claim 1 wherein isotonic soution /buffer solution is phosphate buffer, sodium phospahte dibasic anhyrdous, sodium chloride, sodium sulphiate as an preservative.
5. An intravenous drug delivary system accodring to claim 1 wherein active ingridents are paracetamol and diclofenac sodium.
6. A method for preparation of intravenous drug delivary system comrising;

(a) purging nitrogen gas thorugh water;
(b) dissolving pharamaceutically effective amount of the paracetamol and diclofenac sodium seperatly,
(c) addtion of appropriate amount of sodium phospahte dibasic anhydrous, sodium chloride, sodium sulphaite, 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 delivary system as described with refrence to
description and example herein.