Ramu Krishnan
[2012] APO 41
•4 April 2012
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Ramu Krishnan [2012] APO 41
Patent Application: 2006264407
Title:Improved drug or pharmaceutical compounds and a preparation thereof
Patent Applicant: Ramu Krishnan
Delegate: Nicole Howard
Decision Date: 4 April 2012
Hearing Date: Written submissions provided 14 December 2011
Catchwords: PATENTS – examiner objections – lack of clarity – scope of claims 1-6, 8, 10-12 and 20 indeterminate – 1-8, 11, 12 and 20 not novel – 60 days to amend allowed
Representation: Ramu Krishnan, self represented
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2006264407
Title:Improved drug or pharmaceutical compounds and a preparation thereof
Patent Applicant: Ramu Krishnan
Date of Decision: 4 April 2012
DECISION
Claims 1-6, 8, 10-12 and 20 lack clarity, and claims 1-8, 11, 12 and 20 are not novel. The applicant has 60 days to propose suitable amendments.
REASONS FOR DECISION
1.Patent application 2006264407 was filed by Mr Ramu Krishnan on 29 June 2006 via the PCT claiming a priority date of 4 July 2005. Following five adverse examination reports and three sets of proposed amendments the issue of lack of novelty was still outstanding. The matter was set for hearing on 16 January 2012 with a view to refuse. The applicant has provided written submissions.
The specification
2.The subject of this decision is the specification as proposed to be amended 11 February 2010, 6 April 2011 and 16 August 2011 (hereafter the application) and is titled ‘Improved drug or pharmaceutical compounds and a preparation thereof’.
The specification states ‘…the aim of the present invention is to invent modified molecular structures of the drugs and pharmaceuticals either in the solid form, which are highly soluble in aqueous solutions or non-aqueous solutions of directly in the suitable liquid forms. The present invention emphasizes using organic acids, bases and relevant anion radicals for modifying the drug or pharmaceutical structures into a form wherein it is more bioavailable and bioabsorbable.’
3.It broadly describes a vast array of known compounds which may be reacted with any known pharmaceutical or drug, resulting in complex modified molecules purportedly exhibiting desirable properties. Additional substituents may also be added. Particularly preferred embodiments appear to be modified versions of the cholesterol inhibitors Atorvastatin, Rosuvastatin, Ezetimibe, Sitosterol and Torcetrapib. Several processes for achieving the modified drugs are provided.
4.The application ends with 20 claims (annexed to this decision). Claims 1-11 are directed to modified pharmaceutical or drug molecules. Claim 12 is directed to a process enhancing the solubility, bioavailability and bioabsorbability of known drugs wherein they are reacted with ‘a pre-prepared compound(s) as described herein’. Claims 14, 16 and 18 are directed to a similar process wherein a drug is reacted with specific ‘pre-prepared compound-1’ or ‘pre-prepared compound-2’. Claims 13, 15 and 17 are directed to processes for making ‘pre-prepared compounds 1 and 2’. Claim 19 is directed to chemical work-ups used to prepare products of claim 1. Claim 20 is directed to administering the modified drugs of the invention to reduce their toxicity and/or lower dosage levels.
5.There are numerous grammatical and spelling errors throughout the specification and submissions. When I quote from them I will quote exactly as they appear.
The examiners objection
6.In his fifth report, the examiner has maintained his objection that independent claim 1 is not novel when compared to the disclosures of prior art documents designated below as D1, D2 and D3 and that independent claims 1 and 20 are not novel when compared to D4. Furthermore, the examiner asserted that the additional features in dependent claims 2-8 and 10-11 are ‘either disclosed in any one of D1-D4 or are obvious to a person skilled in the art as these differences reside in what is merely a choice of one of several known alternatives in the art which would be available for use by the person skilled in the art’. The examiner considered the remaining claims to be in order for acceptance.
D1: US 6090800 A (UNGER ET AL) 18 July 2000
D2: EP 1336405 A1 (RANBAXY LABORATORIES, LTD) 20 August 2003
D3: WO 2004/073686 A2 (TEVA PHARMACEUTICAL INDUSTRIES LTD) 2 September 2004
D4: Academic Press – An Imprint of Elsevier, The Practice of Medicinal Chemistry, Edited by Camille G. Wermuth, Second Edition, Chapter 33, Pages 561-563, 2003
I will consider the relevance of these documents below. I must first construe the scope of the claims.
Construction
7.The construction of claim 1 is key to the outcome of this decision. Claim 1 is recited as follows.
1. Modified pharmaceutical or drug molecule exhibiting the synergistic properties of enhanced bioavailability and/or enhanced bioabsorbability and/or enhanced solubility at various pH's preferably from high acidic levels to milder basic levels and/or enhanced absorptivity (increased rate of absorption) and/or decreased toxicity and/or enhanced retentivity of its predecessor in the blood, despite its increased molecular complexity and the said modified drug molecule is obtainable by reacting a known drug molecule whose pharmacokinetic and or pharmacodynamic properties needs to be improved upon and shall be capable of forming chemical bonds such that the said bonds shall be cleavable at the desired sites of a subject, with a pre-prepared compound as herein described and the said pre-prepared compound does not contain Polyethylene glycol moiety.
8.I construe this claim as a modified pharmaceutical or drug exhibiting one or more of the listed desirable properties. These properties are limiting on the scope of the modified molecules because not all products of the reaction defined will inherently possess them. The modified drug is ‘obtainable’ by reacting a known drug molecule (requiring improvement of its pharmacokinetic or pharmacodynamic properties) with a ‘pre-prepared compound as herein described’. The known drug molecule must be capable of forming chemical bonds where the bonds are capable of being cleaved at the desired site in a subject. Polyethylene glycol (PEG) is excluded from being contained in the pre-prepared compound.
9.The construction of the remaining claims will relevantly follow that of claim 1.
What does ‘obtainable’ confer on the scope of the claim?
10.The term ‘obtainable’ limits the modified molecules of claim 1 to any molecule that could potentially result from the reaction defined in the claim. ‘Obtainable’ does not limit the product molecules of claim 1 to those actually produced by the reaction defined in claim 1. That is, a claim to molecules ‘obtainable’ from the specified reaction encompasses structurally identical molecules that could be produced by an entirely different process. This is in sharp contrast to a claim drafted where the modified molecules are ‘obtained’ by carrying out the steps of the reaction.
11.Mr Krishnan argues that if the process is novel then a product when made by that process is also novel. I agree. Indeed, Australian patent law takes the approach that in the case of a ‘product by process’ claim, process features may indeed confer novelty on the claimed product. However, as presently drafted, claim 1 is not limited to molecules when produced by the process. For the claim to be limited by the process features, the modified molecules would need to be ‘obtained’ by the process of the invention. (I note that in his submissions Mr Krishnan has used the terms ‘obtained’ and ‘obtainable’ interchangeably, which tends to suggest he has not fully appreciated the distinction between the two terms.)
12.I find the term ‘obtainable’ does not limit the modified drugs of claim 1 to necessarily being a product made by the process of the invention. It does however restrict the molecules to those that can result from the process.
What kind of chemical bonds are contemplated?
13.The chemical bonds defined in claim 1 ‘shall be capable of forming chemical bonds such that the said bonds shall be cleavable at the desired sites of a subject’, The description does not provide a definition of ‘chemical bond’ and nor does it provide me with any reason other than to construe the term in the context of its plain meaning. In this case a ‘chemical bond’ may include any that is potentially cleavable at a desired site, ranging from ionic bonds through to covalent bonds.
What is a ‘pre-prepared compound as herein described’?
14.Claim 1 directs the reader to determine the meaning of ‘pre-prepared compound’ by reference to the description. The description does not provide an explicit (or even implicit) definition of what is encompassed by a ‘pre-prepared compound’. In the absence of any guidance, the term must be accorded its plain meaning, being a compound that already exists.
15.The applicant submitted that the modified molecules of the invention are limited to those obtainable by treating a drug molecule (capable of binding) with compounds pre-prepared by the novel processes defined in claims 13 and 15. I do not agree. The description provides two examples of pre-prepared compounds designated as ‘pre-prepared compound-1’ (hereafter PC-1) and ‘pre-prepared compound-2’ (hereafter PC-2). These are prepared by the methods of process claims 13 and 15 respectively. I have no doubt that PC-1 and PC-2 clearly fall within the scope of a ‘pre-prepared compound as herein described’. However, while PC-1 and PC-2 may be novel, claim 1 does not limit a ‘pre-prepared compound’ to PC-1 or PC-2. Claim 1 is only limited to modified drugs reacted with a ‘pre-prepared compound’ as described by the specification. The issue to be resolved is exactly what ‘pre-prepared compounds’ are contemplated.
16.The specification is replete with both generalisations and examples of compounds that may be reacted with known drugs to produce the modified molecules of the invention. I make the following non-exhaustive observations drawn from the application:
·Page 2 broadly describes a second aspect of the invention being a ‘process for enhancing the properties like solubility, bioavailability, bioabsorbability of known pharmaceutical or drug having at least one reactable site wherein at least one reactive site is reacted with a pre-prepared compound(s) to obtain a modified form of the said pharmaceutical drug(s) exhibiting the enhanced properties …’. No limitations on the ‘pre-prepared compound’ are provided;
·Avtorvastatin may be linked to an amino acid or a hydroxy poly acid (page 8);
·A drug or pharmaceutical is treated with acid followed by reaction with a relevant anion radical to form a complex compound having high solubility in aqueous/non-aqueous phase (page 8);
·Oil soluble drugs are obtained by linking a long chain fatty acid to the drug amide complex or drug ester complex (pages 8-9);
·Betaine, PEG ‘etc.’ can be used instead of the long chain fatty acid (page 11);
·Enhancing agents that can be used with statins include but are not limited to fatty acids, fatty acid esters, fatty alcohols and amino acids (page 14); and
·It is possible to manufacture a composition comprising a combination of drug molecules bonded with different organic bases and/or with different relevant anion radicals (page 16).
17.It is a difficult task to place a construction on a ‘pre-prepared compound as herein described’. I am satisfied that the term includes at least the compounds used in ‘Examples 1-4’, PC-1, PC-2 and any other compounds (used for modification) specifically named throughout the specification. However, due to the other generalised and often nebulous indications of what compounds are contemplated, I cannot determine the precise ambit of ‘pre-prepared compound’. At its very broadest, it could include anything suitable to achieve the promised modified drugs or pharmaceuticals of the invention. I find the precise scope of the phrase ‘pre-prepared compound as herein described’ indeterminate.
Clarity
18.In order to comply with sec 40(3), the claims must be clear. That is, the meaning and scope of the claims must be capable of precise determination. Indeed, the applicant himself submits ‘It is the duty of the inventor or the applicant to draft the claims in unambiguous manner to the person skilled in the art to perform the invention…’. I sympathise with the applicant when he explains that such a broad invention is difficult to define. However, I have nonetheless found the phrase ‘pre-prepared compound as herein described’ recited in claim 1 cannot be accorded a precise construction. Even if I am incorrect, the matter is further compounded by the use of the term ‘obtainable’, opening the claim up to include a potentially countless number of modified drugs that may be produced from any (suitable) process whatsoever. I therefore must conclude that the scope of claim 1 is not clear.
19.Appended claims 2-6, 8, 10-12 and 20 are also unclear for the same reasons. Claims 7, 9 and 13-19 are considered clear because they contain features which sufficiently resolve the above issues.
20.I also note that appended claims 2, 3, and 11 (when appended to claim 2 or 3) have the same scope as claim 1 due to use of the term ‘optionally’.
Novelty
21.Section 7 of the Act states that an invention is taken to be novel unless it is not novel in the light of the prior art. A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim.
22.It is well established that the general test for lack of novelty is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 at 235:
‘The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement’
23.This test is satisfied if the alleged anticipation discloses all the essential features of the invention as claimed (see Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 517). In order to meet this requirement, the prior art must “contain clear and unmistakeable directions to do what the patentee claims to have invented” (The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 486).
24.The examiner has maintained novelty objections against claims 1-8, 10-11 and 20 based on documents D1-D4. The citations were published before the priority date of the claims at hand. While the precise scope of many of the claims could not be determined, I will nonetheless attempt to assess their novelty using the construction I have provided above. I reiterate that I do not construe a ‘pre-prepared compound as herein described’ as being limited to that prepared by either claim 13 or 15. Regrettably, due to the indeterminate scope of claims 1-6, 8, 10-12 and 20, my novelty finding should not be considered exhaustive.
25.D1 discloses compounds comprising a steroid covalently bonded to a lipid moiety in order to deliver higher concentrations of steroids to target tissue (column 1, line 65 – column 2, line 67). D1 discloses that the compounds are lipid soluble steroid pro-drugs and that they may be used for site specific delivery and targeting to tissues and receptors to improve efficacy and decrease toxicity (column 12, lines 16-42). The lipid moieties are cleavable at the desired site in a subject. Particular steroids considered include norethindrone, hydroxymethylprogesterone and pregnenolone (column 17, lines 1-24). The lipid moieties are fatty acids. Moreover, D1 discloses substituents, excipients and vehicles that may be used to effect the desired characteristic of increased lipid solubility (column 78, line 44 - column 89, line 60). The disclosure of D1 clearly falls within the scope of claims 1-8, 11, 12 and 20.
26.D2 discloses formulations of atorvastatin stabilized with alkali metal additions. The formulations are stated to have improved bioavailability and bioequivalence, and contain the kind of chemical bonds that would be cleavable at the desired sites of a subject, as required by the claims. Claims 1-6, 8, 11, 12 and 20 are anticipated by D2.
27.D3 discloses solutions of simvastatin in menthol that demonstrate improved bioavailability. It does not, however, disclose the modified molecules of the claims which require chemical bonds of the kind that are cleavable at the desired sites of a subject. This document does not anticipate any of the claims.
28.D4 discloses the use of and design of pro-drugs used to improve bioavailability and resistance to metabolic degradation (general introduction, pages 561-562). Furthermore, D4 discloses examples of carrier-pro-drugs such as ampicillin provided as pivampicillin, which provides free ampicillin in the bloodstream rapidly, and improves efficiency and safety (pages 562-563). Moreover, D4 discloses the general carrier-pro-drug system (Figure 33.1, page 562) where a covalent linkage is seen between a drug and a temporary transport moiety (confers for example increased bioavailability) cleavable in vivo for drug action (the carrier-prodrug principle, pages 562-563). D4 anticipates claims 1-6, 11, 12 and 20.
29.In conclusion I find that claims 1-8, 11, 12 and 20 are not novel (notwithstanding that claim 12 was previously found to be novel by the examiner). (Claims 9, 10 and 13-19 are clearly novel.)
Conclusion
30.Claims 1-6, 8, 10-12 and 20 lack clarity, and the invention of claims 1-8, 11, 12 and 20 is not novel. My findings on novelty are only based on what could be construed from the unclear claims. Consequently, two grounds of refusal have been made out.
31.In the present circumstances it is clear that amendments are possible. I allow the applicant 60 days to propose suitable amendments. Any amendments must meet the normal allowability criteria of section 102. That is, an amendment is not allowable at any time if, as a result of the amendment, the specification would claim matter which was not in substance disclosed in the specification as filed. The proposed amendments should at least clarify the term ‘pre-prepared compound as herein described’ and restrict the claims to the subject matter found novel in this decision.
Nicole Howard
Delegate of the Commissioner of PatentsANNEX: The claims as as proposed to be amended 11 February 2010, 6 April 2011 and 16 August 2011..
1. Modified pharmaceutical or drug molecule exhibiting the synergistic properties of enhanced bioavailability and/or enhanced bioabsorbability and/or enhanced solubility at various pH's preferably from high acidic levels to milder basic levels and/or enhanced absorptivity (increased rate of absorption) and/or decreased toxicity and/or enhanced retentivity of its predecessor in the blood, despite its increased molecular complexity and the said modified drug molecule is obtainable by reacting a known drug molecule whose pharmacokinetic and or pharmacodynamic properties needs to be improved upon and shall be capable of forming chemical bonds such that the said bonds shall be cleavable at the desired sites of a subject,with a pre-prepared compound as herein described and the said pre-prepared compound does not contain Polyethylene glycol moiety.
2. A modified pharmaceutical or drug as claimed in claim 1, optionally has plurality of additional substituents than the actual active pharmaceutical or drug component, wherein the said substituents are capable of enhancing the solubility in aqueous and / or non-aqueous solvents / medium, capable of enhancing the bioavailability and bioabsorbability, capable of remaining in solution without precipitating at a varied pH levels of the digestive tract, capable of enhancing the rate of absorption and capable of enhancing retentivity in the blood stream.
3. A modified pharmaceutical or drug as claimed in claim 1 or claim 2, further optionally have plurality of additional substituents than the actual active pharmaceutical or drug component, wherein the said substituents have optionally additional active sites for further complexing the compound.
4. A modified pharmaceutical or drug as claimed in claim 1 whose solubility in aqueous/non aqueous phase is vastly enhanced by first linking the required reactive site(s) of the unmodified drug or pharmaceutical with substituents optionally containing further plurality of reactive sites and next linking with further substituents which aid in improving desired solubility, to this reactive sites, the reactive sites containing amongst Oxygen, Sulphur and/or Nitrogen elements present with/without a lone pair of electron present inside/outside the nucleus.
5. A modified pharmaceutical or drug as claimed in claim 1 prepared from an active pharmaceutical or drug component comprising the active sites, and capable of reacting and forming bond(s) with other chemical entities which when bonded do not alter the mode of action of the said pharmaceutical or drug, wherein the active sites of an unmodified pharmaceutical or drug includes functional groups which comprises atoms like Oxygen, Nitrogen, Sulphur.
6. A modified pharmaceutical or drug as claimed in claim 1 which, notwithstanding it's increased complexicity and higher molecular weight than its predecessor, when orally ingested aids in enabling the drug or pharmaceutical to remain in a more soluble form in the varied pH's of the digestive track and to permeate the digestive track faster, safer and more effectively into the blood stream and also retained better ensuring use of it at a lesser dosage for obtaining a desired performance or use of it at the same dosage for obtaining a better performance, the strength of bonding between the pharmaceutical or drug and the substituent being such that after performing the above function the substituent gets detached and metabolized leaving the active drug to perform its role, wherein the reactive sites of the pharmaceutical or drug molecule comprises of Oxygen, Sulphur and/ or Nitrogen atoms.
7. A modified pharmaceutical or drug as claimed in claim 1 wherein the said modified pharmaceutical or drug has a plurality of acidic groups when the substituent linked is beta hydroxytricarballylic acid, an hydroxyl group when the substituent linked is 2-aminoethanol and/or a long chain fatty acid(s) preferably in bonded combination linked to the active sites of unmodified pharmaceutical compound which exhibits enhanced solubility in the oil phase and helps in permeating through the cell wall at a faster rate.
8. A modified pharmaceutical or drug as claimed in claim 1 wherein the unmodified pharmaceutical or drug is selected from
a) Phytosterol, sterol or stanol including sitosterol, campesterol and stigmasterol, sitostanol and campestanol;
b) a statin preferably acid form of cerivastatin, hydrolyzed acid form of simvastatin, acid form of pravastatin, acid form of fluvastatin, hydrolysed acid form of lovastatin, rosuvastatin, pitavastatin, atorvastatin etc., and derivatives thereof, but most preferably atorvastatin, rosuvastatin, pitavastatin;
c) Des N propionyl form of Torcetrapib, Des di N methyl form of Citalopram, Des di N methyl Escitalopram;
d) Abacavir, Acetaminophen, Acyclovir, Albuterol, Alendronate, Allopurinol, Alprazolam, Amiodarone, Amitriptyline, Amlodipine, Amoxicillin clavulanate, Anastrozole, Amphetamine, Aripiprazole, Aspirin, Atazanavir, Atropine, Atenolol, Atomoxetine, Azithromycin, Baclofen, Benazepril, Benzonatate, Benztropine, Bicalutamide, Bisoprolol, Budesonide, Butalbital, Bupropion, Captopril, Candesartan, Carbamazepine, Carbidopa, Carisoprodol, Cefdinir, Cefprozil, Celecoxib, Cephalexin, Cetraxate, Cetirizine, Chlorpheniramine, Chlorhexidine, Ciprofloxacin, Citalopram, Carvedilol, Clarithromycin, Clindamycin, Clobetasol, Clonazepam, Clonidine, Clopidogrel, Cyclobenzaprine, Desogestrel, Desloratadine, Diazepam, Diclofenac, Digoxin, Diphenoxylate, Diltiazem, Dolasetron, Donepezil, Doxazosin, Doxepin, Doxycycline, Ebastine, Efavirenz, Enalapril, Erythromycin, Ethinyl Estradiol, Etodolac, Escitalopram, Esomeprazole, Ethinyl Estradiol, Ezetimibe, Famotidine, Felodipine, Fentanyl, Finasteride, Fluoxetine, Fexofenadine, Fluconazole, Fluticasone, Furosemide, Fluvastatin, Folic acid, Fosinopril, Gabapentin, Gatifloxacin, Gemfibrozil, Gemcitabine, Glimepiride, Glipizide, Glyburide, Goserelin, Granisetron, Hydrocodone, Hydroxychloroquine, Hydrochlorothiazide, Hydroxyzine, Hyoscyamine, Ibuprofen, Imatinib, Indapamide, indomethacin, Irbesartan, Ipratropium , Isosorbide , Isotretinoin, Ketoconazole, Labetalol, Lamivudine, Lamotrigine, Lansoprazole, Leuprolide, Levodopa, Levetiracetam, Levofloxacin, Levonorgestrel, Levothyroxine, Linezolid, Lisinopril, Lopinavir, Loratadine, Lorazepam, Lcsartan, Lovastatin, Meclizine, Meloxicam, Mesalamine, Metaxalone, Metformin, Methocarbamol, Methotrexate, Methylphenidate, Methylprednisolone, Metoc1opramide, Metoprolol, Mirtazapine, Modafinil, Montelukast, Morphine, Moxifloxacin , Mycophenolate Mofetil, Naproxen, Nelfinavir, Niacin, Nifedipine, Nitrofurantoin, Norethindr'one, Norgestimate, Norgestrel, Nortriptyline, Nystatin, Olanzapine, Olmesartan Medoxomil, Olopatadine, Omeprazole, Ondansetron, Oseltamivir, Oxcarbazepine, Oxybutynin, Oxycodone, Oxcarbazepine, Pantoprazole, Paroxetine, Penicillin, Phenazopyridine, Phenobarbital, Phentermine, Phenytoin, Pioglitazone, Prednisone, Promethazine, Propoxyphene, Propranolol, Quinapril, Quinine, Quetiapine, Rabeprazole, Raloxifene, Ramipril, Ranitidine, Risperidone, Risedronate, Ritonavir, Ritonavir, Rofecoxib, Rosiglitazone, Salmeterol, Sertraline, Sevelamer, Sildenafil, Stavudine, Sumatriptan, Sulfamethoxazole, Tadalafil, Tamoxifen, Tamsulosin, Tegaserod, Temazepam, Testosterone, Temozolomide, Teonfovir, Terazosin, Tetracycline, Terbinafine,Thalidomide, Theophylline, Tizanidine, Tobramycin, Tolterodine, Topiramate, Torcetrapeb, Tramadol, Trazodone, Triamterene, Trimethoprim, Valdecoxib, Valacyclovir, Valproic Acid, Valsartan, Venlafaxine, Verapamil, Warfarin, Zidovudine, Ziprasidone, Zolpidem, Zolmitriptan;
e) any essential or non-essential amino acid / peptide or a precursor of such amino acid or a derivative of such amino acid or a pre-form of such amino acid which is capable of releasing such amino acid as a metabolite either in the digestive tract or at a desired site;
f) a group of metal organic chelates preferably amino acid chelates wherein the metal includes boron, calcium, chromium, copper, cobalt, iron, magnesium, manganese, molybdenum, nickel, potassium, selenium, vanadium and zinc, their derivatives and / or a combination thereof.
9. A modified pharmaceutical or drug as claimed in claim 1 is atorvastatin (S)-2,6-diaminohexanoic acid (Z)-9-octadecenoate; atorvastatin (S)-2,6-diaminohexanoic acid beta hydroxytricarballylate bis 2-aminoethanol di (z)-9-octadecenoiate; atorvastatin octa (S)-2, 6-diaminohexanoic acid hepta betaine; atorvastatin tetra (S)-2,6-diaminohexanoic acid octa 2-Hydroxypropanoate; atorvastatin (S)-2, 6-diaminohexanoic acid beta hydroxytricarballylate bis 2-aminoethanol tetra (Z)-9-octadecenoiate; atorvastatin (S)-2,6-diaminohexanoic acid bis beta hydroxytricarballylate tetra 2-aminoethanol octa (Z)-9-octadecenoiate; atorvastatin hexa beta hydroxytricarballylate tri 2-aminoethanol hexa2-aminoethanol (Z)-9-octadecenoiate tri 2-aminoethanoldi(Z)-9- octadecenoiate; atorvastatin 2-aminoethanol di ethyl beta hydroxytricarballylate; rosuvastatin tetra beta hydroxytricarballylate di 2-aminoethanol tetra2-aminoethanol (z)-9octadecenoiate di 2-aminoethanoldi(z)-9- octadecenoiate; Ezetimibe tetra beta hydroxytricarballylate di 2-aminoethanol tetra 2- aminoethanol (z)-9-octadecenoiate di 2-aminoethanoldi(z)-9- octadecenoiate; Des N propyl torcetrapib beta hydroxytricarballylate bis 2- aminoethanol di (z)-9octadecenoiate; Betasitosterol beta hydroxytricarballylate bis 2-aminoethanol di (z)-9-octadecenoiate.
10. A modified pharmaceutical or drug as claimed in claim 1 is further complexed with Betaine, sarosine or various forms of Lysophosphatidyl like Lysophosphatidyl Choline, Lysophosphatidyl Ethanolamine, Lysophosphatidyl Glycerol, Lysophosphatidyl Serine, Lysophosphatidic Acid, Lysophosphatides in single or in combination.
11. A modified pharmaceutical or drug according to claims 2, 3, 10 wherein the substituent(s) as referred therein is / are selected from the group of Acetic Acid, Adipic Acid, Alanine, Arginine, Ascorbic Acid, Arachidonic acid, Asparagines, Aspartic Acid, Betaine, Benzoic acid, Butanol, Butanoic Acid, Carbonic Acid, Capric acid, Citric Acid, Cysetine, Cystine, Decanoic Acid, Dodecanoic Acid, Ethanol, Ethylene glycol, Ethanolamine, Eicosapentanoic Acid (EPA), Folic Acid, Formic Acid, Fumaric Acid, Gluconic Acid, Glucoheptanoic Acid, Glutamine, Glutamic Acid, Glycirine,Glycine, Betaine, Hexanoic Acid, Hexadecanoic acid Heptanoic Acid, Heptadecanoic Acid, Histidine, Hydroxide, Hydrochloric Acid, Hydroxy Proline, Isolencine, Isopropanol, Lactic Acid, Lauryl Sulphonic Acid, Lactobionic Acid, Leucine, Linoneic Acid, Linolenic Acid, Lysine, Malic Acid, Methionine, Mysteric acid, Nicotinic Acid, Nitric Acid, Nonanoic Acid, Octanoic Acid, Octadecanoic Acid, Octanol, Oleic Acid, Oleyl alcohol, Ornithine, Palmitic Acid, palmitoleic acid, Pentanoic Acid, Pentanol, Phenylalanine, Proline, Propanol, Propionic Acid, Propylene glycol, Phosphoric Acid, Retinoic Acid, Sarcosine, Salicylic Acid, Salicylic Acid Acetate, Serine, Selenious Acid, Stearic Acid, Stearyl alcohol, Succinic Acid, Sulphuric Acid, Tartaric Acid, Tetradecanoic Acid, Threonine, Tryptophan, Tyrosine, Undecanoic Acid, Ursodeoxycholic Acid, Valine or a combination thereof.
12. A process for enhancing the solubility and/or bioavailability and/or bioabsorbability of known pharmaceutical or drug having at least one reactable site wherein at least one reactive site is reacted with a pre prepared compound(s) as described herein to obtain a modified form of the said known pharmaceutical or drug(s) exhibiting the enhanced properties as defined and claimed above.
13. A process of preparing the pre prepared compound as claimed in claim 12 comprises the steps of;
i) reacting one mole of beta hydroxytricarballyllic acid with three moles of 2-aminoethanol such that two of the 2-aminoethanol links to beta hydroxytricarballyllic acid through an acid amide bond and the remaining one mole of 2-aminoethanol links to beta hydroxytricarballyllic acid through an ester bond leaving amino groups free for further reaction.
ii) treating the product of steps (i) with long chain fatty acid halides for example (z)-9-octadecenoic acid chloride wherein the hydrogens of free amino groups present in the product of step(a) is/are replaced with (z)-9-octadecenoic acid moiety.
iii) treating the product of step (ii) with one mole of beta hydroxytricarballyllic acid to obtain a tertiary amine compound,
iv) further treating the product of step (iii) with long chain fatty acid substitutes at nitrogen of 2-aminoethanol to obtain an acid amide derivative as a pre prepared compound- 1.
14. A process for enhancing the properties of solubility, bioavailability, bioabsorbability of
a) atorvastatin wherein mole of atorvastatin is treated with 3 moles of pre prepared compound- 1
b) rosuvastatin wherein 1 mole of rosuvastatin is treated with 2 moles of pre prepared compound- 1
c) ezetimibe wherein 1 mole of ezetimibe is treated with 2 moles of pre prepared compound- 1
as claimed in claim 13.
15. A process of preparing the pre prepared compound' as claimed in claim 12 comprises the steps of; i) reacting one mole of (z)-9-octadecenoic acid with one mole of sulfurous oxychloride to produce (z)-9-octadecenonyl chloride; further reacting two moles of (z)-9-octadecenonyl chloride with one mole of 2- aminoethanol to obtain one mole of 2-aminoethanol bis (z)-9- octadecenoiate; ii) reacting one mole of beta hydroxytricarballyllic acid with three moles of sulfurous oxychloride; Further reacting one mole of the product obtained in this step with two moles of the product obtained in step(i) to obtain one mole of acyl chloride of beta hydroxytricarballylate bis 2-aminoethanoldi(z)-9-octadecenoiate labeled as prepared compound-2.
16. A process for enhancing the properties of solubility, bioavailability, bioabsorbability of
a) atorvastatin wherein 1 mole of atorvastatin (S)- 2,6-diaminohexanoic acid is treated with 1 mole of pre prepared compound-2
b) rosuvastatin wherein 1 mole of rosuvastatin (S)-2,6- diaminohexanoic acid is treated with 2 moles of pre prepared compound- 2 as claimed in claim 15.
17. A process as claimed in claim 13 or claim 15 wherein the solubility of the modified form of known pharmaceutical compound(s) is complete in oil phase and does not separate or precipitate out at a pH from 1 to 8 when dissolved in a aqueous solution with the aid of a known surfactant.
18. A process for enhancing the properties of solubility, bioavailability and bioabsorbability of sitosterol, torcetrapib
a) wherein 1 mole of sitosterol is reacted with I mole of mono acylchloride of beta hydroxytricarbally llic acid «bis 2- aminoethanol di (z)-9octadecenoiate));
b) wherein 1 mole of Des N propionyl form of Torcetrapib is reacted with mole of mono acylchloride of beta hydroxytricarballyllic acid «bis 2aminoethanol di (z)-9- octadecenoiate)).
19. A process to obtain the product of claim 1 wherein when;
(a) the pharmaceutical or drug having carboxylic acid is treated with amino acid having at least one additional amino group for example with (S)2,6-diaminohexanoic acid, to form an amide;
Treating the said amide with hydroxy polyacid such as beta hydroxytricarballyllic acid to form an ester which is further treated with hydroxyl amine like 2-aminoethanol to form an ester which is finally treated with long chain fatty acids to get the final product, the process in which the reactants need not be stoichiometrically equivalents;
OR
(b) the pharmaceutical or drug having amino group is made to react with a polyhydroxy polyacid or with a polyacid or with an amino acid such as glutamic acid to form an amide and the remaining procedure is as same as in step (a) to get the final product;
OR
(c) the phannaceutical or drug having hydroxyl or thiol groups is treated with a polyacid or with a poly hydroxyl polyacid to get an ester, further treated with 2-aminoethanol and followed by the addition of long chain fatty· acids to get the final product of the desired properties.
20. A process of
a) achieving the desired blood level of the active drug or pharmaceutical at an administration of lower dosage level of the active drug or pharmaceutical wherein the lower dosage comprises a suitably modified drug as claimed in anyone of the preceding claims;
b) reducing the toxicity of an active drug by administering the modified drug or pharmaceutical as claimed in the previous claims which contain lower dosage of the active drug or pharmaceutical.
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