WO2002045696A1 - Systeme d'administration de medicament - Google Patents

Systeme d'administration de medicament Download PDF

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Publication number
WO2002045696A1
WO2002045696A1 PCT/GB2001/005420 GB0105420W WO0245696A1 WO 2002045696 A1 WO2002045696 A1 WO 2002045696A1 GB 0105420 W GB0105420 W GB 0105420W WO 0245696 A1 WO0245696 A1 WO 0245696A1
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WO
WIPO (PCT)
Prior art keywords
phase
gelucire
composition
lipophillic
active pharmaceutical
Prior art date
Application number
PCT/GB2001/005420
Other languages
English (en)
Inventor
Duncan Craig
Susan A. Barker
Kah Hay Yuen
Original Assignee
The Queen's University Of Belfast
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Queen's University Of Belfast filed Critical The Queen's University Of Belfast
Priority to AU2002222138A priority Critical patent/AU2002222138A1/en
Publication of WO2002045696A1 publication Critical patent/WO2002045696A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to a drug delivery system. More particularly the invention relates to a formulation which promotes the increased uptake of a drug .
  • the formulation of drugs into tablets or capsules is convenient in relation to packaging and transport, as well as being an easier and safer method to ensure the correct dosage is prescribed.
  • most drugs are crystalline in nature at room temperature and are formulated into dosage forms such as tablets or powder filled capsules using technology that relies on their solid-state properties .
  • Semi-solid or liquid drugs that are non- crystalline or only partially crystalline may not be processed in this manner and alternative strategies are required.
  • lipophillic substances might enhance the absorption of solid state drugs
  • no studies have shown these substances will have a similar effect on the absorption or bioavailability of semi-solid / liquid drugs. This is not a trivial distinction.
  • One of the proposed mechanisms for enhanced absorption of solid state drugs is the partial or complete conversion of the drug to a non-crystalline form, thereby reducing the lattice energy to dissolution. Given that no such barrier exists for liquid or semi-solid drugs (or if one does it is at the very least significantly lower) , such enhancement would not be expected to apply.
  • This study that shows enhanced absorption of one liquid compared to another liquid formulation indicates that the overcoming of solid-solid bonds is not a relevant mode of action of the lipophillic substance.
  • Semi-solid / liquid drugs may be formulated into capsules by filling soft gelatin lock ring capsules with oil based suspensions of the drug, the lock ring of the cap pinching the body of the capsule to form a seal and prevent the oil based suspension from leaking.
  • the separate problems of preparing a practically viable formulation for semi-solid / liquid drugs and devising a method that enhances bioavailability have at present, with the exception of a recently marketed formulation of vitamin E, not been addressed simultaneously.
  • the vitamin E formulation utilises a mix of oils and surfactants to form a liquid formulation with enhanced absorption (Abbot Laboratories) .
  • vitamin E family present dual formulation challenges by being poorly water soluble and liquid at room temperature.
  • Vitamin E The most common naturally-occurring member of the Vitamin E family is ⁇ -tocopherol and its main use is as a source of vitamin E for use in nutraceutical products. It is also used as an antioxidant in pharmaceutical formulations such as Total Parental Nutrition emulsions. It is believed that, due to the antioxidant nature of the vitamin E family, large daily doses of these materials may help to prevent or retard the development of diseases such as cancer and cardiovascular disease by inhibiting the damaging effects of free radicals. Oral absorption of vitamin E is thought to proceed via the formation of mixed bile salt emulsions in the small intestine with consequent absorption into the lymphatic system, hence there is potential for variability absorption depending on the fed/fasted status of the recipient.
  • ⁇ -tocopherol is a liquid at room temperature, thus rendering formulation in a conventional tablet or capsule formulation impractical. It is an aim of the present invention to provide a method of producing a viable dosage form of a liquid/semi solid drug that has enhanced bioavailability but which avoids the drawback of leakage present in the prior art methods.
  • This formulation has the intrinsic advantage of being a solid dosage form and thus does not suffer from problems of leakage.
  • This formulation has further advantages of being simpler and probably cheaper than previous methods of forming formulations with similar characteristics.
  • an advantage of this method is that the technology required to utilise this approach is already available.
  • a solid dosage formulation comprising at least one active agent and a lipophillic phase, wherein the lipophillic phase enables the enhanced absorption of the active ingredients.
  • the active agent may be a semi-solid/liquid drug, pharmaceutical ingredient or nutraceutical wherein these terms include any pharmaceutical compound, drug or composition, including peptides in semi- solid or liquid form.
  • the formulation is a solid dispersion in which the active agent and the lipophillic phase are at least partially phase separated. Preferably greater than or equal to 50% w/w of the active agent is separated from the lipophillic phase.
  • More than one active agent can be included in the formulation at once to yield a desired pharmaceutical composition according the present invention.
  • the formulation containing a semi- solid/liquid active agent can be used in combination with other drugs, pharmaceutical agents or nutraceuticals which are not semi-solid/liquid in composition.
  • the lipophillic phase can be characterised as a mixture of fatty acid esters and glycerides .
  • the glycerides may be a mixture of mono, di-, triglycerides and polyethylene glycol (PEG) mono- diesters.
  • the lipophillic phase is solid at room temperature and liquid at human body temperature.
  • the hydrophilic lipophillic balance (HLB) of the lipophillic phase is less than 16, preferably between 9-14 and advantageously in the neighbourhood of 14.
  • the HLB value can be adjusted by altering the length of the PEG chain.
  • the melting point of the lipophillic phase can be adjusted by altering the length of the chains of the fatty acids and the PEG and by the degree of saturation of the fatty acid chains .
  • the lipophillic phase comprises or is based upon Gelucire ® 44/14 (Gattefosse Corporation, Westwood, N. J. ) .
  • Gelucire 44/14 is one of a family of lipid-based excipients, the Gelucires, comprising a mixture of pegylated fatty acid esters and glycerides, the two numbers of their names corresponding the approximate melting point and HLB value respectively.
  • the active agent is a member of the vitamin E family.
  • the most common naturally- occurring member of the vitamin E family is ⁇ - tocopherol .
  • Both the naturally occurring form, the (R,R,R) isomer, and its synthetic analogue, the racemic d, 1 mixture, are members of the vitamin E family.
  • Also included are the tocotrienols, d and dl ⁇ -tocopheryl acetate and d and dl ⁇ -tocopheryl acid succinate.
  • the active agent may also be Cod Liver Oil.
  • the invention also provides a method of making a semi-solid/liquid pharmaceutical or nutraceutical in a viable dosage form which shows increased absorption.
  • the method includes a step of adding the semi-solid/liquid active pharmaceutical or nutraceutical agent into the melted lipophillic phase. Following addition of the active agent into the molten lipophillic phase the composition is stirred to disperse the active agent within the mixture. The molten liquid is filled into capsules and allowed to set.
  • the Gelucire is melted to between 45 and 65 9 C, preferably 60 a C; the drug is added to the molten Gelucire; and the drug is stirred to disperse it within the mixture.
  • the Gelucire is The molten liquid is filled into capsules and allowed to set.
  • Typical uses of the formulation according to the present invention are clear in in vivo studies of absorption.
  • FIG 1 shows differential scanning calorimetry (DSC) profiles of replicate samples of heat treated Gelucire 44/14.
  • Figure 2 shows DSC profiles of replicate samples of • Gelucire 44/14 alone and with increasing quantities of Vitamin E preparation.
  • Figures 3a) to d) show Hot Stage Microscopy (HSM) images for compositions of a) Gelucire 44/14 alone at 25°C; b) Gelucire 44/14 and 10 %w/w Vitamin E preparation USP at 25°C; c) Gelucire 44/14 and 10 %w/w Vitamin E preparation USP at 55°C; and d) Gelucire 44/14 and 50% w/w Vitamin E preparation USP at 25°C.
  • HSM Hot Stage Microscopy
  • Figure 4 shows the mean (+/- sema) plasma ⁇ - tocopherol concentration versus time profiles of the commercial and Gelucire 44/14 formulations.
  • Solid dispersions containing 10, 25 and 50 % w/w Vitamin E Preparation USP were manufactured as follows. The Gelucire 44/14 was dispensed into a glass vial and placed in a waterbath held at 60 °C for 15 minutes in order to melt the material. It was then allowed to cool for 5 minutes, at which point the Vitamin E Preparation (d- ⁇ -tocopherol 1000 IU/g) USP was added. To minimise solidification prior to adequate mixing, the sample was then placed back in the waterbath (60 °C) for 1 minute, followed by 30 seconds agitation. The sample was then allowed to cool and solidify. Three separate samples were made for each concentration.
  • Liquid-filled hard gelatin capsules were prepared for the 50 %w/w solid dispersions. The process of Example 1 was followed up to the point of agitation and then 600 mg of the molten mixture was filled into the bodies of the size 0 capsules. These were then allowed to cool for 2.5 hours before being capped and stored at ambient temperature until use. Each capsule therefore contained 300 IU of ⁇ - tocopherol. It was observed that no leakage or visible change in appearance was apparent in these capsules after 18 months storage under ambient conditions.
  • DSC Differential scanning calorimetry
  • a scanning rate of 5°C/minute was used over the temperature range -25°C to 65°C. Full calibration was performed prior to the acquisition of experimental data. Baseline calibrations were performed using weight-matched empty pans. Temperature calibration was performed using cyclohexane (theoretical melting point 6.54°C) and n-octadecane (theoretical melting point 28.24°C). A "temperature calibration check" was then performed using n-octadecane.
  • Sample weights of 6.5 to 14 mg were used.
  • the sample and reference pans were loaded into the sample chamber at ambient temperature and the chamber sealed.
  • the sample was then cooled to -25°C, a process taking approximately 5 minutes, and then held at this temperature for 10 minutes.
  • the sample temperature was then increased at 5°C/minute to 65°C.
  • One measurement was made for each combination preparation to give a total of three measurements at each concentration.
  • Gelucire 44/14 alone was studied "as is" and with a preheating step to replicate the production of the combination formulations. In this latter case, the sample and reference pans were placed into the sample chamber at ambient temperature, then heated to 60°C and held there for 15 minutes prior to cooling at 5°C/minute to -25°C.
  • sample temperature ' was increased at 5°C/minute to 65°C.
  • Samples of Gelucire 44/14 alone and the three bulk solid dispersions were tested immediately after manufacture (the time of the test varied from 100 to 130 minutes after manufacture) and at weekly intervals up to 6 weeks post-preparation.
  • Figure 1 shows replicate DSC traces for Gelucire 44/14, previously heat-treated in the manner described above. While. the reproducibility for these samples was satisfactory, it was noted that samples studied as received showed the same basic peak profiles but exhibited poorer reproducibility, demonstrating the necessity for controlling the thermal history of this material in order to obtain reliable results.
  • the trace shows a main peak at circa 42°C with a broad shoulder at approximately 35°C and a smaller secondary peak with a mean peak maximum at 20°C.
  • Gelucire 44/14 is a mixture of materials, it is logical to speculate that the secondary peak and the shoulder on the main peak are due either to melting of specific minor components of the mixture or to mixed crystals formed between different components, rather than different polymorphs of specific materials.
  • Figure 2 shows representative DSC traces of Gelucire 44/14 and the three formulations with Vitamin E Preparation USP . Each individual formulation showed reproducible DSC data. Comparison of the results for Gelucire 44/14 and the mixes shows that the main Gelucire 44/14 peak is retained even as the content of Vitamin E Preparation USP is increased to 50 %w/w. Table 1 illustrates the main peak maximum temperature and the enthalpy of transition for the various samples . There is no change in the peak maximum temperature as the percentage of the drug system is increased, while the enthalpy of the main transition decreases in an approximately linear fashion as the percentage of drug system is increased, although the magnitude of the decrease is not directly proportional to the decrease in Gelucire 44/14 content.
  • Hot Stage Microscopy (HSM) studies were performed using an Olympus BX50 optical microscope fitted to a Linkam temperature controller. Samples were placed on a cover slip and heated at a rate of 5 °C/minute from 25°C to 80°C. The studies were performed on Gelucire 44/14 alone and on the dispersions containing Vitamin E Preparation USP. The results for the Gelucire 44/14 alone are shown in Figure 3a. In essence, a mass of microcrystals is seen which melted over a narrow temperature range at approximately 40 to 45 °C; no distinct events were seen corresponding to the shoulder and the main peak.
  • Figure 3b shows the corresponding image for systems containing 10% w/w Vitamin E Preparation USP. In this case, the droplets of oil are clearly visible as a separate phase that persists beyond the melting of the Gelucire 44/14 ( Figure 3c) . Systems containing 50% w/w drug system also showed separated oil droplets (Figure 3d) .
  • a human volunteer study was carried out comparing the bioavailability of ⁇ -tocopherol from the Gelucire 44/14 formulation to that from a proprietary product containing equivalent amounts of ⁇ -tocopherol.
  • the study was conducted with the approval of the Joint School of Pharmaceutical Sciences, University of Science Malaysia and General Hospital Penang Committee on Bioavailability Studies; all volunteers gave written informed consent.
  • Six healthy adult male volunteers aged between 22 and 38 years old and weighing from 50 to 78 kg participated in a standard two period, two sequence crossover study.
  • the volunteers were not receiving any medication or vitamin E supplements from two weeks before and during the study.
  • the volunteers were randomly divided into two groups of three, with each group taking two capsules of either the proprietary or the Gelucire 44/14 preparation in the first period.
  • each volunteer After a washout period of one week each volunteer then received the alternative product.
  • the total dose of ⁇ -tocopherol per period was therefore 400 mg (approximately 600 IU) .
  • All capsules were given with 240 mL of water at approximately 10 am after an overnight fast. Food and drink (other than water, given ad libitum) were withheld for at least four hours after dosing. Lunch and dinner comprising chicken and rice were served 4 and 10 hours after dosing. Five mL blood samples were collected at 0 (before dosing), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 18, 24, 30 and 36 hours after dosing via an in-dwelling cannula placed in the forearm.
  • the former was calculated using a trapezoidal function and the latter by dividing the last measurable plasma drug concentration with the elimination rate constant (k e ) , calculated from the terminal slope of the individual profiles after logarithmic transformation of the plasma concentration and application of linear regression [Gibaldi, M. and Perrier, D. (1982) "Pharmacokinetics” , 2 nd edition, Marcel Dekker, New York, ppl45-149] .
  • An analysis of variance (ANOVA) procedure that distinguished effects due to subjects, periods and treatments [Wagner, J.G.
  • the absorption of ⁇ -tocopherol appears to be biphasic, particularly for the Gelucire 44/14 product, although this may simply be a reflection of the fact that more ⁇ - tocopherol is being absorbed, hence allowing for a finer disinction of absorption patterns than is possible with the conventional formulation.
  • the second phase of the absorption of ⁇ -tocopherol occurs just after the volunteers were fed (at 10 hours post-dose) and may be due in part to the mobilisation of the lipid-absorbing pathway in response to food.
  • Table 1 The main peak maximum temperatures and enthalpies of transition for mixtures of Gelucire 44/14 and Nitamin E Preparation USP

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne une composition comprenant au moins un principe actif pharmaceutique ou un ingrédient nutraceutique et une phase lipophile, dans laquelle la phase lipophile permet une absorption améliorée du principe actif pharmaceutique ou de l'ingrédient nutraceutique. La phase lipophile est constituée, de préférence, d'un mélange d'esters d'acides gras de polyéthylène glycol et de glycérides.
PCT/GB2001/005420 2000-12-07 2001-12-07 Systeme d'administration de medicament WO2002045696A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002222138A AU2002222138A1 (en) 2000-12-07 2001-12-07 Drug delivery system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0029843.0 2000-12-07
GBGB0029843.0A GB0029843D0 (en) 2000-12-07 2000-12-07 Drug delivery system

Publications (1)

Publication Number Publication Date
WO2002045696A1 true WO2002045696A1 (fr) 2002-06-13

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GB (1) GB0029843D0 (fr)
WO (1) WO2002045696A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023249A1 (fr) * 2003-09-03 2005-03-17 Boehringer Ingelheim International Gmbh Nouvelle forme galenique orale pour ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyle)-phenylamino]-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino]propionique et ses sels
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
CN103169676A (zh) * 2011-12-23 2013-06-26 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞舌下片及其制备方法
US9278065B2 (en) 2007-08-09 2016-03-08 Ems S/A Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
CN103169676B (zh) * 2011-12-23 2016-12-14 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞舌下片及其制备方法
CN109512787A (zh) * 2018-12-07 2019-03-26 天津国际生物医药联合研究院 一种维生素b12固体分散体及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4869900A (en) * 1985-02-01 1989-09-26 Zambon S.P.A. Pharamaceutical composition containing ubidecarenone
US5993858A (en) * 1996-06-14 1999-11-30 Port Systems L.L.C. Method and formulation for increasing the bioavailability of poorly water-soluble drugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4869900A (en) * 1985-02-01 1989-09-26 Zambon S.P.A. Pharamaceutical composition containing ubidecarenone
US5993858A (en) * 1996-06-14 1999-11-30 Port Systems L.L.C. Method and formulation for increasing the bioavailability of poorly water-soluble drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KHOO SHUI-MEI ET AL: "The formulation of Halofantrine as either non-solubilising PEG 6000 or solubilising lipid based solid dispersions: Physical stability and absolute bioavailability assessment.", INTERNATIONAL JOURNAL OF PHARMACEUTICS (KIDLINGTON), vol. 205, no. 1-2, 2000, pages 65 - 78, XP001062701, ISSN: 0378-5173 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8470347B2 (en) 2000-05-30 2013-06-25 AbbVie Deutschland GmbH and Co KG Self-emulsifying active substance formulation and use of this formulation
US8268349B2 (en) 2003-08-28 2012-09-18 Abbott Laboratories Solid pharmaceutical dosage form
US8309613B2 (en) 2003-08-28 2012-11-13 Abbvie Inc. Solid pharmaceutical dosage form
US8333990B2 (en) 2003-08-28 2012-12-18 Abbott Laboratories Solid pharmaceutical dosage form
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8399015B2 (en) 2003-08-28 2013-03-19 Abbvie Inc. Solid pharmaceutical dosage form
US8691878B2 (en) 2003-08-28 2014-04-08 Abbvie Inc. Solid pharmaceutical dosage form
WO2005023249A1 (fr) * 2003-09-03 2005-03-17 Boehringer Ingelheim International Gmbh Nouvelle forme galenique orale pour ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyle)-phenylamino]-methyle-1-methyle-1h-benzimidazol-5-carbonyle)-pyridine-2-yle-amino]propionique et ses sels
US9278065B2 (en) 2007-08-09 2016-03-08 Ems S/A Delivery systems for solubilising water-insoluble pharmaceutical active ingredients
CN103169676A (zh) * 2011-12-23 2013-06-26 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞舌下片及其制备方法
CN103169676B (zh) * 2011-12-23 2016-12-14 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞舌下片及其制备方法
CN109512787A (zh) * 2018-12-07 2019-03-26 天津国际生物医药联合研究院 一种维生素b12固体分散体及其制备方法

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AU2002222138A1 (en) 2002-06-18

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