US20160339085A1 - Pharmaceutical composition containing a mixture of proenzymes and enzymes - Google Patents

Pharmaceutical composition containing a mixture of proenzymes and enzymes Download PDF

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US20160339085A1
US20160339085A1 US15/037,331 US201415037331A US2016339085A1 US 20160339085 A1 US20160339085 A1 US 20160339085A1 US 201415037331 A US201415037331 A US 201415037331A US 2016339085 A1 US2016339085 A1 US 2016339085A1
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pharmaceutical composition
composition according
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composition
glycerol
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Frantisek Trnka
Pavel Dolezal
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
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    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
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    • A61K38/46—Hydrolases (3)
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/18—Carboxylic ester hydrolases (3.1.1)
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2405—Glucanases
    • C12N9/2408—Glucanases acting on alpha -1,4-glucosidic bonds
    • C12N9/2411—Amylases
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6427—Chymotrypsins (3.4.21.1; 3.4.21.2); Trypsin (3.4.21.4)
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    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
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    • C12Y302/01001—Alpha-amylase (3.2.1.1)
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    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21004—Trypsin (3.4.21.4)

Definitions

  • the invention deals with new pharmaceutical compositions containing a mixture of proenzymes and enzymes having anti-proliferative and anti-metastatic effects.
  • Malignant neoplastic diseases represent a vast group of diseases that are one of the worst curable death causes. They cause 13 percent of deaths per year recently. (Jemal A. et al., CA: Cancer J. Clinic., 61, 2011, 69-90.). Occurrence of malignant tumours brings dangers given by the ability of tumour cells to change adjacent cells while new blood vessels, further supporting cells and metastases are produced.
  • Anti-neoplastic pharmacotherapy is an important part of large spectrum of present treatment approaches.
  • pharmacotherapy of neoplastic diseases is divided to adjuvant (affecting so called residual disease e.g. after a surgical operation), non-adjuvant (preceding operation and radiation treatment, aimed at tumour devitalisation and inhibition) and metro therapy (long-term application of minimum doses of cytostatics affecting neoangiogenesis in advanced forms of neoplastic diseases.
  • Antimetabolites, mitotic inhibitors, hormonal function inhibitors, reactive radical substances, photosensitizers, DNA alkylation agents, DNA separation spindle interactors, intercalators and topoisomerase inhibitors, tubulin and microtubules, attacking substances, inhibitors of cancer growth signals and proliferation are described there in the list of substances and mechanisms.
  • Cancer treatment success varies a lot today depending on particular malignity type.
  • Some types of cancer diseases e.g. testicular seminoma, infant leukaemia, and some lymfoms are very sensitive to anti-neoplastic treatment (Gonzalez-Angulo, A. M et al., Adv. Exp. Med. Biol., 608, 2007, 1-22).
  • Other malignant cancer diseases show a limited response only (if any) and no efficient therapy is available against them now. (Jemal, A. et al., CA Cancer J. Clin., 60, 2010, 277-300). In the instances of advanced tumours with developed metastases, chemotherapy remains palliative treatment in better cases.
  • Resistance against anti-neoplastic medicines represents another serious problem, particularly in long-term treatment (Redmond, K. M. et al.: Front. Biosci., 13, 2008, 5138-5154), whether based internally in tumour cells (intrinsic resistivity) or it is acquired. Multiple resistance against higher number of anti-neoplastic substances, often of different structures and functions, appears more and more often (Wu, Ch.-P. et al.; Curr. Pharm. Biotechnol., 12, 2011, 609-620). This clinical resistance is multifactorial and heterogeneous with numerous molecular mechanisms. (Glickman, M. S., Sawyers, C., Cell 148, 2012, 1089-98). Relatively short history of targeted biological cancer treatment has already been filled with wide spectrum of resistances (Gorre, M. E. et al., Science 293, 2001, 876-880).
  • ATC 3 and ATC 4 are supramolecular active substances mainly of biotechnological origin. They belong to so called biopharmaceuticals, today biologics, protein therapeuticals, and each of them has actually a potential to affect hundreds of physiological processes in a patient (Yang, J. A.; Hastings Sci. Tech. L. J., 3, 2011, 217, 1-18), which represents substantial growth compared to medicines with small molecule.
  • the risks of immune responses include hypersensitiveness, anaphylaxis, pseudoallergic anaphylactoid reaction, series disease, reaction to infusion, therapeutic effect reduction (Borges, S.
  • the solution is based on a pharmaceutical composition containing a mixture of proenzymes and enzymes, containing proenzymes trypsinogen and chymotrypsinogen and enzymes ⁇ -amylase and lipase as active substances, and one or more pharmaceutically acceptable excipients, for simultaneous, separate and subsequent administration of the composition in parenteral or transmucosal way, while the composition has anti-proliferative and anti-metastatic effects to cancer tumours and is intended for therapeutic, prophylactic and anti-metastatic use in mammals.
  • the pharmaceutical composition has advantageous ratio of enzymatic active substances, namely activities of trypsinogen (T), chymotrypsinogen A (CH), ⁇ -amylase B.s (A) and lipase T.a. (L) for T:CH:A:L ratio expressed in m.u. in the range from 150:150:40:1 to 400:1200:200:1
  • the above pharmaceutical composition advantageously contains trypsinogen of type I, chymotrypsinogen of type A, ⁇ -amylase is produced by Bacillus sp. and lipase is from Triticum aestivum.
  • the minimum enzymatic activity of active substances in the pharmaceutical composition according to the invention is advantageously as follows: trypsinogen 40 m.u./mg, chymotrypsinogen 60 m.u./mg, ⁇ -amylase 20 m.u./mg and lipase 1 m.u./mg.
  • At least one of the active substances in the pharmaceutical composition according to the invention is advantageously replaced with biologically similar substance obtained by extraction from higher plants, animals or by cultivation procedures using mould cells, yeast cells, or bacteria, the primary structure of the biologically similar substance with the active substance which it has replaced in the composition being at least 70% identical and the position of active places essential for the effect is at least in 95% identical.
  • composition according to the invention is particularly suitable for systemic sublingual, rectal, inhalation or parenteral administration.
  • the pharmaceutical composition according to the invention may contain numerous substances as pharmaceutically acceptable excipients, particularly one or more hydrophilic polyhydric alcohols including polyethylene glycol with mol. weight 100 to 8000 and/or hydrophilic low molecular alcohols like glycerol, propylene glycol, n-propanol, and/or saccharides like trehalosa, mannitol, lactose, sorbitol, myo-inositol, and/or polysorbates like polysorbate 20, polysorbate 60, polysorbate 80, poloxamers like poloxamer 182, poloxamer 417, poloxamer 908, and/or one or more lipophilic excipients including hydrogenated triglycerides like hydrogenated glycerol trioleate, hydrogenated glycerol-cocoate, and/or esters of higher fatty acids with glycerol or propylene glycol like glycerol-tripalmitate, glycerol-trioleate,
  • the pharmaceutical composition is designed for sublingual administration, it is advantageously in the form of nanofibres, while it contains at least one of polyvinyl polymers like polyvinylpyrrolidone with molecular weight approx. 30 to 50 thousand and polyvinyl alcohols with molecular weight from 20 thousand to 200 thousand, of cellulose derivatives like methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and/or polysaccharides of starch type like hydroxyethyl starch, carboxymethyl starch sodium salt and/or dextrins with molecular weight from 4 000 to 80 000 and/or of biotechnological polysaccharides of dextran type with molecular weight from 10 000 to 80 000, and/or glucuronate type substances like xanthan mucilage, and/or further polyuronides especially their salts, particularly sodium, potassium, like hyaluronans, alginans, pectinans, arabinans and/or polymers based on acrylic, me
  • composition or its part is designed for inhalation administration it advantageously also contains at least one or more saccharides, including trehalose, mannitol, glucose and/or various forms of lactose.
  • saccharides including trehalose, mannitol, glucose and/or various forms of lactose.
  • composition according to any of the claims may advantageously be in the form of nanofibre stabilized preparation for direct administration of active substances or as stabilized storage of active substances in an intermediate product or in the final preparation.
  • proenzymes and enzymes representing a substantial modification of enzyme therapy by its composition and efficiency. It solves the main side effects of present oncologic treatment based particularly on impact on lively divided healthy tissues like gastrointestinal system mucous membrane, medulla, liver and kidney parenchyma. This is thus targeted biological therapy in the real sense of the word, non-toxic, selectively focused on tumour cells, wide spectral from the point of view of anti-neoplastic effects. It impacts on carcinomas, sarcomas, as well as acute haematological malignity.
  • Dosage of the therapeutic composition is only limited by the minimum daily dose in relation to the volume of degrading elements originating from tumour cells. Thanks to the intrinsic non-toxicity of the composition according to the invention, where particularly, or only degrading products from decomposed tumour cells may have toxic effect, the composition may also be used for diagnostic purposes and actually with regard to the experience gained from application of in vivo methods of testing the efficiency on lines of tumour cells grown on mice it is obvious that the composition according to this application will have anti-neoplastic effect not only in humans, but its effect against tumours affecting animals, e.g. a dog or a cat may also be anticipated. However their different anatomy as well as immunogenicity has to be taken into account, while such influences can hardly be predicted.
  • the minimum daily dose means such a quantity of the anti-neoplastic composition that ensures full or partial therapy of a tumour diseases or the required diagnostic or prophylactic effect with regard to the current state of the tumour disease and in relation to the chosen administration method.
  • Stabilization of the individual components of the anti-neoplastic four-composition according to this application is solved for the purpose of elaboration into a pharmaceutical preparation and for the administration purposes by means of excipients and procedures ensuring preservation and actually regeneration of the secondary and higher supramolecular structures of the partial active components.
  • Systemic administration in non-invasive ways which may be advantageously applied to the anti-neoplastic composition according to the invention solves one of the important today's problems of biologic medicine administration (biologics, protein therapeutics etc.), which is the short plasmatic half-time of these substances in organism.
  • biologic medicine administration biologicals, protein therapeutics etc.
  • the new solution according to the invention is fundamental, empirically observed from influences on trophoblast as a biologic model of malignant tumours even at the molecular level (Soundarajan, R., Rao, J., Reprod. Biol. Endocrinol., 2, 2004, 15 (http://www.rbej.com/content/2/1/15, on line: 30.6.2013;).
  • the solution is based on classic concept of J. Beard (Beard, J.: Lancet 168, 1905, 281-283), who proposed treatment of advanced carcinomas by fresh pancreatic extracts. Their antitumoural activity was based on proteolytic potential.
  • pancreatic extracts should have similar inhibition effects to invasive tumours.
  • extract from pancreatic enzymes were thoroughly examined for that time. It was found that they really very efficiently inhibit cancer growth even in patients at advanced stage of malignant neoplasm (Goeth, R. A., J. Am. Med. Assoc. 1907; 1030). With regard to several subsequent reports on negative effects of administration of then very imperfectly processed pancreatic extracts the research was abandoned for a long period (Gurchot, Ch., Oncology 31, 1975, 310-333). Later traceable exceptions from recent years (e.g. Maeda et al.: EU Pat. 0215 662 A2, 1986) only mention proteases, not protease proenzymes, zymogens.
  • Trnka at al. also discovered (Novak, J., Trnka, F.: Anticancer Res., 25, 2005, 1157-77), that continuous exposition of tumour cells to low concentration of the above substances leads to formation of cell aggregates and inhibition of metastases. He managed to combine the historic data with new findings and he deduced that
  • protease proenzymes are resistant to inactivation of protease inhibitors, (b) proenzyme activation only occurs in tumoral cell membrane, (c) active serine proteases destroy cell surface of tumoral cells, they have apoptotic effect, which are the substantial findings on which this invention is based.
  • One of the characteristics of the invention is thus yet not described integration of lipase enzyme into anti-neoplastic composition and its wide-spectral efficiency newly distributed and confirmed by us.
  • protease proenzymes instead of active proteases is based on the existence of plasma anti-proteases, which together with proteases form complexes that prevent protease penetration to tumoral cell surface (Currie, G. A., Bagshawe, K. D., Lancet 279 (7492), 1967, 708-10).
  • These anti-proteases are particularly alpha-1 antitrypsin and alpha-2 macroglobulin (Lah, T. T. et a., Expert Opin. Biol. Ther., 6, 2006, 257-279), for which proenzymes are illegible.
  • pancreatic secretory inhibitor PSTI
  • pancreatic acinar cells pancreatic secretory inhibitor
  • Nonparticipation in hemocoagulation cascade and invasive character of malignant tumours is another advantage of proenzyme application. Thanks to trypsin activity of malignant tumours protease proenzymes are selectively activated on tumour cells. This property of proenzymes circumventing the anti-protease protective effect does not affect tumour cells in vitro, where it is unimportant whether active proteases or their proenzymes are used. By in vitro trials we have demonstrated aggregative impact on tumour cells and by further in vivo trials also inhibitive impact on tumoral proliferation and metastases in several crucial lines of human tumour cells.
  • Amylase effect on tumour cells is thus being studied again as well as the role of trypsinogen and chymotrypsinogen (Itkonen, O., Scandin. J. Clin. Lab. Invest., 70, 2010, 136-143; Koskensalo, S. et al.: Oncology 82, 2012, 234-241) and effect of lipases (Nomura, D. K. et al., Cell 140, 2010, 49-61), namely triacylglycerol hydrolases, EC 3.1.1.3 as serine proteases, whose combined use is the principle of the effect of the four-composition according to this invention application.
  • the anti-metastatic effect of the therapeutic, diagnostic and prophylactic composition according to the invention is newly extended and boosted compared to the above state of the art by addition of vegetable lipase (Aub, J. C, Tieslau, C., Natl. Acad. Sci. USA, 50, 1963, 613-619), characterized at the active point by a triad of histidine-asparagine amino acids.
  • the wide-spectral anti-neoplastic effect of the new composition is given by its new structure, which accepts the complex relations in living organism of humans or animals. It does not prevent occurrence of tumour cells, however it destroys tumour cells that have already appeared, which restores and maintains complex balances of biological environment in normal healthy condition, limits occurrence and propagation of oncogenic signals.
  • the principle of prophylactic utilization of the anti-neoplastic composition according to the invention may be basically described analogically. With regard to the minimum own toxicity of the preparation a period of administration of therapeutic doses of the composition may be included in the process of patient oncology monitoring. If tumour cells and thus the substrate for the activity of the preparation components were present in the organism the preparation administration would in fact already provide its effect prophylactically with the above accompanying symptoms.
  • the solution according to the invention is based on composition of two proenzymes of trypsinogen and chymotrypsinogen group with alpha-amylase and lipase (hereinafter also collectively referred to as active substances) defined from activity point of view.
  • This four-composition shows in in vivo conditions surprisingly substantial positive effects towards wide spectre of tumour cells of completely different histological characteristics, as mentioned above, both after injection subcutaneous administration and non-invasive transmucosal, particularly rectal administration.
  • composition according to the invention represents a combination of enzymes and proenzymes obtained by extraction from organs (tissues) of animals (particularly mammals), plants and/or substances produced by cultivation methods using moulds and microorganisms or e.g. by continuous perfusion of mammal cells and consequent supernatant processing. With improvement of separation and analysis methods the proportion of cultivation process products is growing.
  • Proteins and polypeptides which are carefully taken from their natural environment, separated and identified.
  • Contaminants originating from natural material may affect therapeutic, diagnostic and prophylactic use of proteins and polypeptides. They may contain not only protein components, but also numerous contaminants of various characters. They may lead to change of the original natural protein composition particularly to its glycosylation, secondary change or change of higher supramolecular structures, which might lead to undesirable immune or other reactions when administered to living organism. It is considered proven nowadays that not only the primary structure of proteins decides on their final interactions in organism, but obviously particularly the secondary and tertiary structures of proteins, which are in direct physical and chemical interactions with biological environment.
  • composition according to the invention is not based on weight, but on enzymatic activity units.
  • the individual substances of the anti-neoplastic composition can be described by these characteristics and the extent of similarity of possible variations within that the same effects of both the partial components and the anti-neoplastic composition as a whole can be subsequently defined.
  • Necessary stabilization of the anti-neoplastic composition for the purpose of its elaboration into the pharmaceutical preparation is based on stabilization of the individual components. These components have to be assessed and evaluated as non-immunogenic for processing to the usable preparation and its administration. Their stabilization for processing and application is solved by using excipients and procedures that from the point of view of the present state of technology ensure preservation (or regeneration) of secondary and higher supramolecular structures of the partial active components and thus the four-composition according to our application as a whole (Lee, G.: Spray drying of proteins, in: Carpenter, J. Manning M. (Eds.), Rational Protein Formulation: Theory and Practice. Plenum Press, New York, 2002, 135-158).
  • medium-chain triglycerides Hauss, D. J., Adv. Drug Deliv. Rev.; 59, 2007, 667-76; Tan, A., Rao, S., Prestidge, C. A.; Pharm. Res., 2013, 1-25
  • selected surfactants e.g. dipalmitoylphosphatidylcholine, polysorbates, polyoxyethylene stearates (Mansour, H. M., Damogna, S., Zografi, G.: Mol. Pharm., 5, 2008, 681-695
  • cryoprotectants e.g.
  • glycerol ethylene glycol, propylene glycol, dimethyl sulfoxide; hydroxyethyl starch, polyvinylpyrrolidone (Meryman H. T.; Cryobiology 8, 1971, 173-183).
  • PEGs polyethylene glycols
  • the solution of the anti-neoplastic mixture according to the invention in given context thus uses information published on purification, regeneration a stabilization of supramolecular structures, namely for all partial components of the composition according to the invention (Pellegrini-Malpiedi, L., Picó, G. A, Nerli, B. B., Separ. Purif. Technol., 78, 2011, 91-96; Porfiri, M. C. et al.: Int. J. Biol. Macromol., 49, 2011, 7-13; Bassani, G. et al.; J. Chromatogr. B, 859, 2007, 222-228).
  • PEGs polyethylene glycols
  • composition of the mixture and its dosage may be modified in details according to chosen application way and consequently also according to the vehicle used for the particular active substance, and dosage in clinical conditions may be defined and optimized according to the current state of the tumour disease or according to organism response to administered dose.
  • the anti-neoplastic composition according to the invention basically enables outpatient treatment approach. It moreover enables self-administration particularly when non-invasive administration methods are used, and use of corresponding preparation types e.g. for sublingual or rectal administration. We consider both these ways advantageous for administration of the composition according to the invention as well as inhalation method through lung alveolar walls. Good tolerance to the preparation and absence of allergic symptoms or other negative immunological or other biological responses of the patient are certainly the basic conditions.
  • Injection preparations with prolonged or otherwise modified active substance release which release the active substance slowly and for longer period after administration, where it is desirable, e.g. in intraperitoneal application may also be used.
  • Further excipients of which both slowly degraded lipids and biodegradable polymeric systems based on proven polymers or oligomers of glycol acid, lactic acid and their co-polymers (Chaubal, M. V. et al.: Excipient selection and criteria for injectable dosage forms.
  • Kathdare, A., Chaubal, M. V. Excipient Development for Pharmaceutical, Biotechnology and Drug Delivery Systems. InformaHealthcare, New York, London 2006, 271-290
  • Gokarn, Y. R. et al Excipient for protein drug. 291-331.
  • Kathdare A., Chaubal M. V. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems. InformaHealthcare, New York, London 2006, 291-331
  • alveolar epithelium which is the most penetrable and in terms of useful area of the alveoli absolutely the largest mucosal surface, should be the most suitable from this point of view.
  • Inhaled low molecular medicine may appear in system circulation in seconds, which is very close to intravenous administration. This trait of inhalation application is however not important for the composition according to the invention. The effect start time in seconds or minutes is not important in this case, and for macromolecular substances it is unachievable. The second, but more important factor in this relation is the fact that penetration of inhaled particles through the complicated tree of branching bronchi and bronchioles up to the alveolar surface has already been satisfactorily solved.
  • composition according to the invention meets requirements for processability into the inhalation powder form both without further excipients and with suitable carrier (e.g. trehalose, lactose, mannitol), polyethylene glycol type substance of lower and medium molecule weight (e.g. macrogol 300 or macrogol 1500) and their mixtures.
  • suitable carrier e.g. trehalose, lactose, mannitol
  • polyethylene glycol type substance of lower and medium molecule weight e.g. macrogol 300 or macrogol 1500
  • composition according to the invention is also suitable for processing into lipid micro particles, where their stabilizing and handling advantages and particularly advantageous properties as application systems for protein inhalation administration (Chow, A. H. L. et al., Pharm. Res. 24, 2007, 411-437; Mehnert, W., Mider, K.: Adv. Drug Deliv. Rev. 64, 2012, 83-101) may become useful.
  • Analogous statement also applies to formulation-technological aspect of the individual partial methods of parenteral administration. We particularly applied subcutaneous injection administration of those documented in the application.
  • Other partial methods of parenteral administration of the composition according to this patent application e.g. intraperitoneal, intrathecal are further possible considered variants (Huynh, G. H., Deen, D. F., Szoka, F. C., J. Control. Rel., 110, 2006, 236-259). They are well manageable from formulation-technological point of view, however the exact immunological properties of all the substances used, i.e. immunologic purity of the components of the composition according to the invention and of course the appropriate biologic response will be decisive for their use.
  • sublingual administration method which in principle enables as fast (or slightly faster) commencement of medicine effect as subcutaneous injection administration, is relatively advanced. Its basic advantage is that it ensures slower and longer transfer to the system circulation to substances with large molecule (e.g. 50,000). We can thus actually talk about sublingual infusion.
  • Such sublingual administration has a substantial advantage against parenteral, including subcutaneous administration. This is the fact that substances after absorption through sublingual mucous membrane are not taken by the bloodstream directly to the liver, where they are mostly metabolised and deactivated, but they avoid the liver first-pass effect. The path and time of their movement in organism are thus much longer and enable non metabolised substances to reach to more distant parts of the body. This is why we consider sublingual method very advantageous also for administration of the anti-neoplastic composition according to the invention.
  • a brand new type of sublingual preparation (new dosage form) suitable for biologics thanks to its composition and properties is based on application of nanofibre membranes (Stránská, D. et al.: Pat CZ 303 244; 2012).
  • nanofibre membranes By their design and by using suitable pharmaceutically acceptable polymers they help avoid usual problems of other sublingual products, particularly their interaction with saliva or swallowing substantial part of the medicine.
  • These nanofibre membranes have excellent mechanical properties, they usually enable up to 50 percent of active substances, including biologics, to be incorporated directly into the fibres. Even higher weight percentage of active substances may be anchored by impregnation. In mass production they are advantageously produced e.g. by means of electrospinning.
  • the anti-neoplastic composition according to the invention may be factually processed not only into nanomembranes for direct application of the active substances, but also into stabilized intermediate product and biologics type products for stock, all that actually without loss of biological activity of the active substances (e.g. of protein, polypeptide, virus or bacteria type).
  • rectal administration method provides the same advantages in terms of first-pass effect avoidance and longer transport range for nonmetabolised therapeutic molecules. Except for minor problems, which are absolutely negligible with regard to the sense and importance of rectal administration of the anti-neoplastic combination according to the invention, this method can be definitely considered advantageous as we have repeatedly demonstrated for the composition according to the invention by the above mentioned in vivo trials.
  • Rectal systemic administration of medicines is traditionally used, well proven, backed by relatively wide selection of excipients and suitable manufacturing technologies. It may use conventional excipients, i.e. non-ionic substances from the group containing neutral lipids, e.g. tri-, di- or monoesters of higher fatty acids and polyols, e.g. glycerol, polyoxyethylene glycerides, e.g. polyoxyethylene glycol glyceryl-cocoate, polyoxyethylene glycols, polyethylene glycol ethers and higher fatty alcohols, e.g. lauryl alcohol, polyoxyethylene polar oils, e.g.
  • excipients i.e. non-ionic substances from the group containing neutral lipids, e.g. tri-, di- or monoesters of higher fatty acids and polyols, e.g. glycerol, polyoxyethylene glycerides, e.g. polyoxyethylene glycol glyceryl-
  • ricin oil oil saccharo-glycerides, polyethylene oxide and propylene oxide copolymers and their mixtures, if necessary with selected anti-oxidants (e.g. tocopherols, ascorbic acid, their derivatives like tocopheryl ascorbate) and further auxiliary substances.
  • selected anti-oxidants e.g. tocopherols, ascorbic acid, their derivatives like tocopheryl ascorbate
  • Co-administration principle can be used to reach the effective levels of the anti-neoplastic composition in the organism. This means administration of all the composition parts in such amounts that ensure effect at the same time with regard to the application method or at different moments by means of one application preparation or more application preparations. This may be a single “co-administration” or multiple administrations at particular intervals. With the possibility to use various methods of administration a part of the composition may be administered by one of the possible methods (e.g. rectally) and the other part necessary to reach effective levels of the composition in the organism may be administered by different method, e.g. sublingually or parenterally.
  • the essential innovation of the solution according to the invention is based on yet not described integration of lipase enzyme into an anti-neoplastic composition and its proven wide-spectral effectiveness.
  • the newly designed composition of the preparation shows in in vivo trials a sum of activities bringing a complex, surprisingly strong cellular anti-tumoral effects. This finding is based on the results obtained from in vivo trials on nu/nu mice with subcutaneously implanted cells of standardized lines of human mamma carcinoma, colorectal carcinoma, pancreatic carcinoma and small-cell lung carcinoma.
  • composition definition based on enzymatic activity units, not on weight proportions of the individual active substances as it is in earlier remotely similar patents (Trnka et al, 1996, 1998, see above).
  • This approach to efficiency definition ensures technical feasibility of the invention and reproducibility of composition of the active substances, and thus also of the appropriate manners designed for their administration to organism.
  • Today's pharmacopoeias include requirement for using the activity characteristics for enzymes.
  • stearoyl polyoxyl-6-glycerid stearoyl polyoxyl-6-glycerid
  • neutral lipids e.g. glyceryl-palmitostearate
  • esters of monovalent alcohols with higher fatty acid e.g. isopropyl-myristate, isopropyl-palmitate
  • permeation enhancers e.g., glycerol, cyclopentadecanolide, polycarbophil-cysteine.
  • FIG. 1 shows a part of photo documentation visually comparing the treated and untreated mouse with subcutaneously transplanted MDA-MB-231 line of mamma carcinoma in 36-day in vivo trial in everyday rectal administration of the anti-neoplastic composition.
  • FIG. 2 shows graphic interpretation of average values of tumour volumes (including SD) in 36-day in vivo trial on nu/nu mice with subcutaneously transplanted MDA-MB-231 line of mamma carcinoma in everyday subcutaneous and rectal administration of the anti-neoplastic composition according to this application (composition K1, or K2 according to Table 1); female nu/nu mice; approx. 28 g; 8 mice in each group; lipophilic suppository vehicle; dose 2 represents double quantity of K2 composition.
  • FIG. 3 shows a part of photo documentation visually comparing the treated and untreated mouse with subcutaneously transplanted H 116 line of colorectal carcinoma in 75-day in vivo trial in everyday rectal and subcutaneous administration of the anti-neoplastic composition.
  • FIG. 4 shows graphic interpretation of average values of tumour volumes (including SD) in 75-day in vivo trial on nu/nu mice with subcutaneously transplanted H 116 line of colorectal carcinoma in everyday subcutaneous and rectal administration of the anti-neoplastic composition according to this application; female nu/nu mice; approx. 28 g; 8 mice in each group; lipophilic suppository vehicle.
  • FIG. 5 shows a part of photo documentation visually comparing the treated and untreated mouse with subcutaneously transplanted CAPAN 2 line of pancreatic carcinoma in 85-day in vivo trial in everyday subcutaneous and rectal administration of the anti-neoplastic composition.
  • FIG. 6 shows graphic interpretation of average values of tumour volumes (including SD) in 85-day in vivo trial on nu/nu mice with subcutaneously transplanted CAPAN 2 line of pancreatic carcinoma in everyday subcutaneous and rectal administration of the anti-neoplastic composition according to this application; female nu/nu mice; approx. 28 g; 8 mice in each group; lipophilic suppository vehicle.
  • FIG. 7 shows a part of photo documentation visually comparing treated and untreated mouse with subcutaneously transplanted A 549 line of small-cell lung carcinoma on the 40th and 85th day of in vivo trial in everyday administration of the anti-neoplastic composition.
  • FIG. 8 shows graphic interpretation of average values of tumour volumes (including SD) in an in viva trial with subcutaneously transplanted A 549 line of small cell lung carcinoma in everyday rectal administration of the anti-neoplastic composition (K2 according to Table 1) female nu/nu mice; approx. 28 g; 8 mice in each group; hydrophilic suppository vehicle.
  • Amylasa Alpha-amylasa from Bacillus sp. Type II-A, lyophilised powder. Isolated from Bacillus amyloliquefaciens . Sigma-Aldrich. Prague. Product No.: A 6380; EC No. (Sigma): 232-560-9; EC No.: 3.2.1.1; CAS No.: 9000-90-2
  • Chymotrypsinogen ⁇ -Chymotrypsinogen A from bovine pancreas. lyophilised powder, without salt content. Applichem. Prague. Product No.: A069
  • Trypsinogen Trypsinogen from bovine pancreas. Dialyzed and lyophilised powder, without salt content. Sigma-Aldrich. Prague. Product No.: T1143; EC No. (Sigma): 232-651-3; CAS No.: 9002-08-8
  • the individual components of the composition can be processed according to usual rules as powder mixture and then as an intermediate product towards the required dosage form.
  • Individual finely ground components may also be gradually integrated to a prepared vehicle or its part for the purpose of primary processing with suitable carrier (e.g. trehalosa for injection administration, see Example 12, stabilizing excipient (e.g. n-propanol, polyethylene glycol 300) or complete vehicle (hardened fat with added isopropyl-myristate as suppository base) according to particular intended application (see Example 8 and Example 9)
  • suitable carrier e.g. trehalosa for injection administration, see Example 12
  • stabilizing excipient e.g. n-propanol, polyethylene glycol 300
  • complete vehicle hardened fat with added isopropyl-myristate as suppository base
  • Specific quantity of the therapeutic composition required for administration of one dose to a human depends on characteristics of the particular individual (weight, age, health condition parameters including individual reactivity to the administered composition), anti-neoplastic disease characteristics (e.g. type, location, stage) administration method (e.g. systemic sublingual, parenteral infusion, systemic rectal), way of application (e.g. monotherapeutic, sequential, graded) and preparation physical character (e.g. colloid solution, separated powder mixture).
  • characteristics of the particular individual weight, age, health condition parameters including individual reactivity to the administered composition
  • anti-neoplastic disease characteristics e.g. type, location, stage
  • administration method e.g. systemic sublingual, parenteral infusion, systemic rectal
  • way of application e.g. monotherapeutic, sequential, graded
  • preparation physical character e.g. colloid solution, separated powder mixture
  • Examples 2.1, 3.1, 4.1, and 5.1 represent sequences of amino acids of enzymatic and proenzymatic substances for anti-neoplastic compositions according to Example 1 and Table 1.
  • Related reference examples 2.2, 2.3, 3.2 a ⁇ hacek over (z) ⁇ 3.4, 4.2, and 5.2 represent sequences of amino acids of representatives of biologically similar substances that may be used as substitutes for substances according to Table 1 as so called “biosimilars” namely individually or in the complete structure. Maintaining the effect quality the individual enzymatic activities of the components in relation to protein weight unit are always important for such biologically similar compositions prepared this way. This characteristic is one of the factors deciding on suitability of an alternative “biosimilar” composition for a particular or considered application.
  • Composition 1 2.239 Trehalose 25.00
  • the mixture is prepared as mixture lyophilised powder containing Composition 1 as per Table 1 with structural stabilizing trehalose, subsequently aseptically distributed in 100 vials.
  • Preparation packing contains an ampoule with water vehicle of this content (mg/100 ml):
  • Water vehicle is for ex tempore preparation of 3 millilitres of solution from dry lyophilised powder.
  • Appropriate dose of Composition 1 in the resulting solution of volume 3 millilitres is then applied by droplet infusion of suitable composition e.g. with dextran 10,000.
  • Specific therapeutic, diagnostic or prophylactic dosage of the composition is based on complex oncologic examination of particular individual.
  • Composition 1 2.580 (see Tab. 1) Polyethylene glycol 4000 5.160
  • the mixture is prepared as mixture lyophilised powder containing Composition 1 as per Table 1 and stabilizing polyethylene glycol 4000 and subsequently aseptically distributed in 100 vials.
  • Preparation packing contains an ampoule with solution of 8 mg of sodium chloride in 1 ml of water for injection.
  • Specific therapeutic, diagnostic or prophylactic dosage of the composition is based on complex oncologic examination of particular individual.
  • Composition 2 2.563 Isopropyl-palmitate or 1.9 Stearoyl polyoxyl-6-glyceride Hardened fat 180.0
  • composition 2 is administered as a hydrophobic suppository in one morning dose.
  • Specific therapeutic, diagnostic or prophylactic dosage of the composition is based on complex oncologic examination of particular individual.
  • composition 2 2.563 n-propanol or glycerol 1.9 Polyethylene glycol 300 95.0 Polyethylene glycol 1500 85.0
  • composition 2 according to Table 1 is administered as a hydrophilic suppository in one morning dose, or in a half dose in the morning and half dose at noon.
  • Specific therapeutic, diagnostic or prophylactic dosage of the composition is based on complex oncologic examination of particular individual.
  • Composition 3 3.11 Trehalosa 10.0 Glycerol 85% buffered to pH 7.4 3.5 Hydroxypropyl methyl cellulose 2.2 Polyethylene glycol 400 1.1 Redistilled water q.s.
  • the nanofibrous sublingual preparation is administered in the morning and in the evening after meal as adhesive film on the bottom side of tongue.
  • Specific dosage of the composition is based on complex oncologic examination of particular individual.
  • composition 3 3.11 Mannitol 10.0 n-propanol buffered to pH 7.4 3.5
  • Polyethylene oxide 400 1.1
  • the resulting two-layer preparation is applied by the protective polyurethane layer towards the mouth cavity and by the hydroxypropyl methyl cellulose reservoir of Composition 3 to the sublingual side.
  • the nanofibrous sublingual preparation is administered in the morning and in the evening after meal as adhesive film on the bottom side of tongue.
  • Specific therapeutic, diagnostic or prophylactic dosage of the composition is based on complex oncologic examination of particular individual.
  • Composition 4 2.73 Trehalose 20.00 Water for injection to 100.0
  • the obtained powder is prepared for processing, filling and application in dose powder inhaler (e.g. of Turbhaler, Easyhaler, Novolizer, Certihaler type) or as pressurized powder (e.g. in Ultrahaler or MAG-haler type inhalers), or in a single-dose system with pre-adjusted powder capsules (e.g. Spinhaler, Aerolizerk, Handihaler), or powders in multi-dose capsule or blister systems (e.g. Diskhaler or Diskus).
  • dose powder inhaler e.g. of Turbhaler, Easyhaler, Novolizer, Certihaler type
  • pressurized powder e.g. in Ultrahaler or MAG-haler type inhalers
  • pre-adjusted powder capsules e.g. Spinhaler, Aerolizerk, Handihaler
  • powders in multi-dose capsule or blister systems e.g. Diskhaler or Diskus.
  • the powder composition for reconstitution for inhalation is aseptically distributed in ten glass injection bottles to 100 ml while the content of Composition 4 is 48.2 mg.
  • reconstitution 1 bottle is filled with water for injection or sterilized water. Nebulisation is performed in a suitable small e.g. jet based, vibrating membrane or electronic nebuliser of e.g. Spag-2, PARI LC Star, Aero-Eclipse or Pro-Dose type.
  • a suitable small e.g. jet based, vibrating membrane or electronic nebuliser e.g. Spag-2, PARI LC Star, Aero-Eclipse or Pro-Dose type.
  • Composition 5 2.239 (see Tab. 1) Trehalose 20.00
  • the above Formula is processed as mixture lyophilised powder containing Composition 5 according to Table 1 and structural stabilizing trehalose distributed into 100 vials.
  • Specific dosage of the composition is based on complex oncologic examination of particular individual.

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US11185587B2 (en) 2021-11-30
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