WO2015137872A1 - Système d'administration de médicament en forme de feuille ou tubulaire - Google Patents

Système d'administration de médicament en forme de feuille ou tubulaire Download PDF

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Publication number
WO2015137872A1
WO2015137872A1 PCT/SE2015/050279 SE2015050279W WO2015137872A1 WO 2015137872 A1 WO2015137872 A1 WO 2015137872A1 SE 2015050279 W SE2015050279 W SE 2015050279W WO 2015137872 A1 WO2015137872 A1 WO 2015137872A1
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WO
WIPO (PCT)
Prior art keywords
drug delivery
medicament
delivery system
temperature
delivery element
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PCT/SE2015/050279
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English (en)
Inventor
Helena CEWERS
David Wensbo Posaric
Original Assignee
Innovator Skåne Ab
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.)
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Application filed by Innovator Skåne Ab filed Critical Innovator Skåne Ab
Publication of WO2015137872A1 publication Critical patent/WO2015137872A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time

Definitions

  • the present invention relates to a novel tubular or sheet-shaped drug delivery system for water triggered administration of medicament, in particular within a body cavity or to the skin or mucous membranes.
  • All drugs and pharmaceutically active compounds are associated with a concentration range, at their site of action, within which the most desirable effect is achieved.
  • This range has a lower limit equivalent with the lowest concentration at which the desired pharmacological effect is achieved, and an upper limit defined by the concentration at which unacceptable adverse effects become noticeable.
  • this range may vary over time as dependant on the particular disease or condition which is treated or in any other way affected by the drug or active compound. For example, a relative high concentration of a drug which initiates sleep is desirable in the CNS when the patient is awake and desires to fall asleep. When the patient has fallen asleep, the drug has completed its task and, in the ideal case, it is desirable that the concentration is zero in order to avoid any potential side effect, i.e.
  • the upper ideal limit has decreases to zero at the time when the patient falls asleep.
  • a medicament in the form of a controlled release formulation may be administered by several different routes, e.g. orally or via the skin or mucous membranes.
  • the latter two routes may be preferred, for example, in applications where a local high concentration of the medicament is desired or in order to e.g. circumvent a high first pass metabolism of a metabolically sensitive drug.
  • WO2005035012 describes a wound dressing in the form of e.g. a foam, matrix, paste or hydrogel, comprising an absorbent material that may absorb wound exudate and one or several therapeutic ingredients contained in liposomes.
  • the liposomes may be such adapted that they interact with wound constituents, e.g. phospholipases expressed by bacteria in the wound or proteases, to release a therein contained therapeutic ingredient to the wound.
  • Disadvantages of this controlled release system include its limited use to applications in which specific triggers with an ability to interact and initiate release from liposomes are present.
  • W09811877 describes a dry powder composition comprising liposome encapsulated active ingredient, e.g.
  • an anti-inflammatory agent e.g. an anti-inflammatory agent
  • a water absorptive carrier or matrix e.g. modified starch and maltodextrin. Release of the active ingredient is triggered by e.g. moisture by water absorption assisted release of the liposomes. Disadvantages of this controlled release system include the cumbersome or limited possibility to remove the powder from e.g. the skin, should an interruption of the exposure to the active ingredient be desired.
  • WO2005055964 describes a free floating powder composed of water sensitive micro-spheres with encapsulated fragrance for incorporation in e.g. cosmetic products such as deodorants, sticks, soaps, powders and sprays.
  • the water sensitive material comprise of water soluble and water dispersible synthetic and natural polymers and copolymers, e.g. polyvinyl alcohol.
  • Disadvantages of this controlled release system include the cumbersome or limited possibility to remove the powder from e.g. the skin, should an interruption of the release of fragrance be desired.
  • WO0195888 describes a bioadhesive tablet that is activated by moisture and which may stay attached in e.g. the buccal or vaginal cavity for an extended period of time during which active ingredient, e.g. testosterone or progesterone, is delivered.
  • the tablet comprises a water insoluble polycarboxylic polymer, e.g. polycarbophil, and a water soluble polymer, e.g. carbomer 974P.
  • Disadvantages of this controlled release system include the limited possibility of adaption to accomplish a rapid wetting of the entire system, should a high release of active ingredient be desired.
  • the present invention seeks to mitigate, alleviate, circumvent or eliminate at least one, such as one or more, of the above-identified deficiencies.
  • a drug delivery system for water triggered administration of medicament having an elongated tubular form adapted for placement in a body cavity or being shaped as a sheet adapted for placement on a surface of the body, comprising a drug delivery element, wherein the drug delivery element is having a passive essentially dry state and an active moist state; the drug delivery element is comprising an essentially water insoluble hydrophilic carrier matrix being a porous or fibrous polysaccharide and a set of additional components being (i), (ii), (iii) and (iv), or (iv) and (v), wherein (i) being at least one protonated positively or deprotonated negatively charged form of the medicament, (ii) being at least one negatively or positively charged counterion accompanying the protonated positively or deprotonated negatively charged form of the medicament, respectively, to maintain electric neutrality, (iii) being a base
  • the active moist state being a state in which the total water content of the drug delivery element exceeds e.g. 10 %, by weight.
  • the carrier matrix may comprise cellulose or modified cellulose.
  • Advantages of cellulose or modified cellulose in this application includes the readily availability, the low cost, and the well known medical properties.
  • each existing component of (i), (ii), (iii), (iv) and (v) may be immobilized at a temperature below a first temperature, said first temperature being a temperature being equal to or exceeding about 25°C, when the drug delivery element is existing in the passive essentially dry state by: each existing component of (i), (ii), (iii), (iv) and (v) may exist in a solid form or a semisolid form, by being entrapped in another solid or semisolid form of another component selected from (i), (ii), (iii), (iv) and (v) by being dissolved, dispersed, emulsified or suspended therein, or by strong molecular interaction or covalent binding thereto, or by being attached to the carrier matrix by strong molecular interaction or covalent bonding.
  • a pharmaceutically acceptable carrier with such properties include the ability of controlled immobilization of components by enclosure therein, e.g. as a solid solution or dispersion, which components, e.g. medicaments, would otherwise have a possibility of unwanted leakage from the drug delivery element due to their e.g. inherent volatile or liquid properties.
  • components e.g. medicaments
  • air sensitive components e.g. air sensitive medicaments
  • the pharmaceutically acceptable carrier or the corresponding may have a phase transition temperature associated with the transition from a solid or semisolid form to a liquid form at a temperature which is equal to a second temperature, the second temperature being a temperature which is lower than or equal to e.g. 37°C, when the drug delivery element is existing in the active moist state.
  • Advantages of a carrier with such properties include the necessity of fulfilment of one additional requirement associated with the temperature of the surrounding, beside the requirement of existing in the active moist state, for release of medicament from the drug delivery system.
  • the second temperature is a temperature which is slightly lower than normal body temperature but higher than ambient or room temperature, e.g.
  • the set of additional components may comprise (i), (ii), (iii) and (iv).
  • the base or acid may be attached to the carrier matrix by strong molecular interaction or covalent bonding.
  • Advantages of such attachment to the carrier matrix include, for example, the possibility of immobilization of basic or acidic medicaments, respectively, in the carrier matrix as their corresponding solid salts, with a minimized release of the corresponding counterion when the drug delivery element is brought to its activated moist state.
  • the counterion might e.g. be preferred with respect to a relatively high long term stability of the corresponding salt form of the medicament, but disfavored by e.g. having a relatively high inherent toxicity.
  • corresponding drug delivery element decreases advantageously the antimicrobial activity at the site of application, as well as being more intimately attached thereto, whereby a more effective transport of medicament to the target tissue may
  • the additional component (i) may be at least one protonated positively charged medicament; the additional component (ii) may be at least one negatively charged counterion; the additional component (iii) may be a base; and the additional component (iv) may be selected from one or several of the group
  • the drug delivery system may be used for administration of the medicament to mucous membranes, or for transdermal or local administration of the medicament to the skin.
  • the medicament may have a pharmaceutical effect at a location of the body, e.g. skin or mucous membrane, which is different or the same as the location of the body onto which the drug delivery system is placed when in use.
  • a location of the body e.g. skin or mucous membrane
  • the medicament may be selected from the group consisting of medicaments with at least one basic functional group, medicaments with at least one acidic functional group, medicaments with no essentially basic or acidic functional groups, i.e. neutral medicaments, and zwitterionic medicaments.
  • the drug delivery system may be used for administration of the medicament to the female reproductive organs.
  • the medicament of the drug delivery system may be at least one local anaesthetic.
  • the medicament of the drug delivery system may be an eutectic mixture comprising at least one pharmaceutically active ingredient, which mixture is having an eutectic point in the moist state at a temperature being less than the second temperature.
  • the medicament of the drug delivery system may be an eutectic mixture comprising at least one pharmaceutically active ingredient, such as an eutectic mixture of two pharmaceutically active ingredients, e.g. prilocaine and lidocaine or other well known eutectic mixtures, which mixture is having an eutectic point, e.g. in the moist state, at a temperature being equal to or lower than the second temperature.
  • eutectic mixture of two pharmaceutically active ingredients e.g. prilocaine and lidocaine or other well known eutectic mixtures
  • Advantages of the combination of ingredients to generate such eutectic mixtures include the potential release of medicament in a concentrated liquid form, e.g. when the melting point of one or both of the pure components of the eutectic mixture exceeds e.g. normal body temperature or the second temperature.
  • the drug delivery system may comprise an integrated container adapted to contain water or an aqueous solution for enabling provision of water to the drug delivery element, e.g. upon a voluntarily active action taken by the user or patient, to accomplish transition from the passive essentially dry state to the active moist state.
  • the user or patient may thus, in a highly practical way, initiate administration of medicament at will.
  • Other user controlled ways of initiating administration of the prior-art include the swallowing of a tablet, the smearing of a paste or ointment on the skin or the preparation and application of an adhesive plaster.
  • the solution according to the invention involves a simple momentarily application of pressure to the system, which represents an optimal or alternative way in the sense of user friendliness.
  • the drug delivery system may comprise a or at least one pressure sensitive conduit or valve having an inlet connected to the container and an outlet connected to the drug delivery element, the conduit or valve may be adapted to be closed at a pressure being less than a first internal pressure of the container to prevent liquid transfer from the container to the drug delivery element, and the conduit or valve may be adapted to be open at a pressure exceeding a second internal pressure of the container to permit liquid transfer from the container to the drug delivery element, for user initiated transition from the passive essentially dry state to the active moist state by application of external pressure to the container to increase the internal pressure thereof.
  • the drug delivery system may comprise a conduit or valve having an inlet connected to the container and an outlet connected to the drug delivery element, wherein the conduit or valve may be provided with a temperature sensitive and essentially water insoluble plug having a melting point within the range of e.g. 30°C to 40°C, the plug being solid at a temperature below its melting point to prevent liquid transfer from the container to the drug delivery element, and the plug being liquid at a temperature above its melting point to permit liquid transfer from the container to the drug delivery element.
  • a drug delivery system comprising such a temperature sensitive valve represents a condition initiated drug release system, the condition being exceeding a temperature threshold being equal to or less than the temperature within the bodily cavity, or of the area of the body, e.g.
  • the drug delivery system will remain in a passive essentially dry state, wherein no or minimal medicament is released, until it is placed in a bodily cavity, or onto the area, whereby the drug delivery system attains an active moist state leading to release of medicament.
  • the user needs to undertake no other action but placing the drug delivery system at the site of action, i.e. within a body cavity or on the skin or mucous membrane, to achieve the desired exposure to the medicament. Until that event, the content of the drug delivery system, including the medicament, remains in a dormant state associated with advantages described elsewhere herein.
  • FIG. 1 is an overview of schematic illustrations used in the drawings, in which
  • A, “A-”, “B”, “B+”, “C”, “I-”, “M”, “M-” and “M+” represents an acid in a neutral form, an acid in a negatively charged form, a base, a base in a positively charged form, a pharmaceutically acceptable carrier, a negatively charged counterion, a positively charged counterion, a medicament in a neutral or zwitterionic form, a medicament in a negatively charged form and a medicament in a positively charged form, respectively, a cluster of multiple irregular threads (A) represents a carrier matrix in a passive dry state, a cluster of multiple irregular threads with a plurality of accompanying water (“H 2 0") molecules (B) represents the carrier matrix in an active moist state, a square represents a solid or semisolid state of matter, e.g. a solid or semisolid acid (C), a circle represents a liquid state of matter, e.g. a liquid
  • an irregular continuous shape represent a dissolved state of matter, e.g. a negatively charged counterion in solution (E), an "R" with an indicative arrow ("R->") is used to indicate a singularity or plurality of elements which may be released from the drug delivery element of the invention, e.g. a liquid pharmaceutically acceptable carrier being released (F), a shape encompassed by another shape indicate the matter of the former shape to be e.g. dissolved, dispersed, emulsified or suspended in the matter of the latter shape, e.g.
  • a dispersion of a solid or semisolid medicament (G) or a dissolved medicament (H) in a liquid pharmaceutically acceptable carrier a dashed line ending with a dot is used to indicate matter attached by strong molecular interaction or covalent bonding, e.g. an attached solid or semisolid base (I) or an attached positively charged base being pseudo-dissolved in the surrounding environment (J);
  • Fig. 2A is a cross section view from the side of a drug delivery element 100 in a dry state, comprising a pharmaceutically acceptable carrier in a solid state with an immobilized solid medicament dispersed therein, according to one embodiment;
  • Fig 2B is the drug delivery element 100 of Fig. 2 A during the transition from its dry to its moist state by absorption of water in the form of e.g. sweat or any other aqueous secretion from the lower side, showing the release of liquid medicament and in a liquid pharmaceutically acceptable carrier dissolved medicament, according to one embodiment;
  • Fig. 3A and 3C is a view of a drug delivery element 100 in its dry state comprising a positively charged medicament, a negatively charged counterion and a base in an immobilized solid form (A), and a negatively charged medicament, a positively charged counterion and an acid in an immobilized solid form (C), according to two embodiments;
  • Fig. 3B and 3D is a view of the drug delivery element 100 of Fig 3A and 3C in the corresponding moist state, respectively, comprising a neutral or zwitterionic medicament in a liquid form which is being released, a negatively charged counterion in a dissolved form and a positively charged base in a dissolved form (B), and a neutral or zwitterionic medicament in a liquid form which is being released, a positively charged counterion in a dissolved form and a negatively charged acid in a dissolved form (D), according to two embodiments;
  • Fig. 4A is a view of a drug delivery element 100 in its dry state comprising a positively charged medicament, a negatively charged counterion and a base in an immobilized solid form, all dispersed in an immobilized pharmaceutically acceptable carrier in a solid form, according to one embodiment;
  • Fig. 4B is a view of the drug delivery element 100 of Fig. 4A in a moist state, showing a positively charged base and negatively charged counterion, both being dissolved partly is the aqueous environment of the carrier matrix and partly in a liquid form of the pharmaceutically acceptable carrier, and a liquid form of medicament and a in a liquid form of the pharmaceutically acceptable carrier dissolved form of
  • Fig. 4C is a view of the drug delivery element 100 of Fig. 4A in a moist state, showing positively charged base and negatively charged counterion, both being dissolved partly is the aqueous environment of the carrier matrix and partly in a liquid form of the pharmaceutically acceptable carrier, and a in a liquid form of the
  • Fig. 4D is a view of the drug delivery element 100 of Fig. 4A in a moist state, showing positively charged base and negatively charged counterion, both being dissolved partly is the aqueous environment of the carrier matrix and partly in a liquid form of the pharmaceutically acceptable carrier, and a liquid form of medicament being released from the drug delivery element 100, according to one embodiment;
  • Fig. 5 A is a view of a drug delivery element 100 in its dry state comprising a positively charged medicament in an immobilized solid form, a negatively charged counterion in an immobilized solid form and a base bound to the carrier matrix, according to one embodiment;
  • Fig. 5B is a view of the drug delivery element 100 of Fig. 5 A in a moist state, showing the medicament in a liquid form being released, a negatively charged counterion in dissolved form, and a positively charged base bound to the carrier matrix and being pseudo-dissolved in the aqueous environment of the carrier matrix, according to one embodiment;
  • Fig. 5C is a view of a drug delivery element 100 in its dry state comprising a positively charged medicament in an immobilized solid form dispersed in an
  • immobilized solid form of a pharmaceutically acceptable carrier a negatively charged counterion in an immobilized solid form dispersed in an immobilized solid form of the pharmaceutically acceptable carrier, and a base bound to the carrier matrix and being partly dispersed in an immobilized solid form of the pharmaceutically acceptable carrier and partly existing in a solid form outside of the pharmaceutically acceptable carrier, according to one embodiment;
  • Fig. 5D is a view of a the drug delivery element 100 of Fig. 5C in a moist state, showing a neutral or zwitterionic form of the medicament being released partly as a liquid form and partly as a in a liquid form of the pharmaceutically acceptable carrier dissolved form, a negatively charged counterion partly dissolved in the aqueous environment of the carrier matrix and partly in a liquid form of the pharmaceutically acceptable carrier, and the positively charged base partly pseudo-dissolved in the aqueous environment of the carrier matrix and partly in a liquid form of the
  • Fig. 6A is a view of a drug delivery element 100 in its dry state comprising a neutral or zwitterionic medicament in an immobilized solid form dispersed in an immobilized solid form of a pharmaceutically acceptable carrier, according to one embodiment;
  • Fig. 6B is a view of a the drug delivery element 100 of Fig. 6A in a moist state, showing a neutral or zwitterionic form of the medicament being released partly as a liquid form and partly as a in a liquid form of the pharmaceutically acceptable carrier dissolved form, and an additional amount of medicament being dissolved in a liquid form of the pharmaceutically acceptable carrier, according to one embodiment;
  • Fig. 6C is a view of a the drug delivery element 100 of Fig. 6A in a moist state, showing a neutral or zwitterionic form of the medicament being released as a liquid form, and a liquid form of the pharmaceutically acceptable carrier remaining within the carrier matrix, according to one embodiment;
  • Fig. 6D is a view of a the drug delivery element 100 of Fig. 6A in a moist state, showing a neutral or zwitterionic form of the medicament being released as a solid dispersed in liquid form of the pharmaceutically acceptable carrier, and a part of the medicament remaining as a solid dispersed in a liquid form of the pharmaceutically acceptable carrier which is remaining within the carrier matrix, according to one embodiment;
  • Fig. 7A and 7B are cross sectional views from the side of a drug delivery system having an elongated tubular form comprising a drug delivery element 100 in a dry state (A), wherein a pressure sensitive conduit or valve 102 is closed by being pressed together 105 so that water in container 103 is prevented from flowing to and reaching drug element 100, and in a moist state (B), wherein an applied external pressure 104 is causing the pressure sensitive conduit or valve 102 to open by not being pressed together whereby a flow 106 of water is reaching the drug delivery element 100 causing a transition to a moist state, whereby medicament is released in various forms as described herein from the drug delivery element 100 via a drug permeable outer element 101, which is enclosing the drug delivery element 100, the container 103 and the pressure sensitive conduit or valve 102, according to one or two embodiments;
  • Fig. 8A and 8B are cross sectional views from the side of a drug delivery system having an elongated tubular form comprising a drug delivery element 100 in a dry state (A), wherein a conduit or valve 102 is closed by being plugged with a solid temperature sensitive and essentially water insoluble plug 107 so that water in container 103 is prevented from flowing to and reaching drug element 100, and in a moist state (B), wherein a relatively high temperature is causing the conduit or valve 102 to open by melting of the temperature sensitive and essentially water insoluble plug 107, which thereby becomes a liquid 107, whereby a flow 106 of water is reaching the drug delivery element 100 causing a transition to a moist state, whereby medicament is released in various forms from the drug delivery element 100 via a drug permeable outer element 101, which is enclosing the drug delivery element 100, the container 103 and the pressure sensitive conduit or valve 102, according to one or two embodiments;
  • Fig. 9A and 9B are cross sectional views from the side of a drug delivery system having an elongated tubular form comprising a drug delivery element 100 with an exposed distal end and a proximal end enclosed by an outer element 101 in a dry state at a temperature below the melting point of the material of plug 107, wherein a conduit or valve 102 is closed by being plugged with a solid temperature sensitive and essentially water insoluble plug 107 so that water in container 103 is prevented from flowing to and reaching drug element 100 (A), and in a dry state, wherein a pressure sensitive conduit or valve 102 is closed by being pressed together 105 so that water in container 103 is prevented from flowing to and reaching drug element 100 (B), according to two embodiments;
  • Fig. 10 depicts the generic formula of examples of various suitable materials
  • formula (I) represents triglycerides of glycerol and independently selected short (R is comprising 1 to 5 carbon atoms), medium (R is comprising 6 to 11 carbon atoms) or long (R is comprising 12 to 33 carbon atoms) carboxylic acid residues, in which each residue independently may be saturated or unsaturated with 1 to 4 double bonds
  • formula (II) represents the corresponding monoglycerides
  • formula (III) represents the corresponding diglycerides
  • formula (IV) represents the corresponding free fatty acids
  • formula (V) and (VI) represents ethers comprising independently selected polyethylene glycol moieties, in which m and n are integer numbers independently selected from the ranges of 0 to 30 and 1 to 30, respectively, formula (VII) and (VIII) represent mixed
  • Formula (IX) and (X) represent exemplary small molecular additives, according to various embodiments of the invention.
  • Fig. 11 A andl IB are cross sectional views from the side of a sheet formed drug delivery system comprising a sheet formed drug delivery element 100 with an exposed distal end and a proximal end adjacent to an outer element 101 in a dry state at a temperature below the melting point of the material of plug 107, wherein a plurality of conduits or valves 102 are closed by being plugged with a solid temperature sensitive and essentially water insoluble plug 107 so that water in container 103 is prevented from flowing to and reaching drug element 100 (A), and in a dry state, wherein a plurality of pressure sensitive conduits or valves 102 are closed by being pressed together 105 so that water in container 103 is prevented from flowing to and reaching drug element 100 (B), according to two embodiments;
  • Fig. 12A is the drug delivery element of Fig. 11 A in an active moist state wherein a relatively high temperature has caused the conduit or valve 102 to open by melting of the temperature sensitive and essentially water insoluble plug 107, which thereby becomes a liquid 107, whereby a flow 106 of water is reaching the drug delivery element 100 causing a transition to a moist state, whereby medicament is released in various forms from the exposed distal end of the drug delivery element 100, e.g. to a contacting area of the skin of a patient, according to one embodiment; and
  • Fig. 12B is the drug delivery element of Fig. 1 IB in an active moist state wherein an applied external pressure 104 to the outer element 101 has caused the pressure sensitive conduit or valve 102 to open by not being pressed together whereby a flow 106 of water is reaching the drug delivery element 100 causing a transition to a moist state, whereby medicament is released in various forms from the exposed distal end of the drug delivery element 100, e.g. to a contacting area of the skin of a patient, according to one embodiment.
  • the drug delivery system of the invention essentially comprises a drug delivery element 100, being adapted to withhold or release the medicament, i.e. drug, as dependent on the amount of water present therein, and an outer element 101, adapted to fully or partly enclose the drug delivery element 100 and optionally other elements of the drug delivery system.
  • the medicament resides in a dormant non-releasable storable form when the drug delivery element 100 is essentially dry, i.e. when existing in a passive essentially dry state.
  • the medicament may be immobilized in the passive state by existing in a solid salt-form or by being dissolved, dispersed, emulsified or suspended in another element, e.g.
  • a solid or semisolid pharmaceutical acceptable carrier which resides in the drug delivery element 100.
  • additional examples of ways by which the medicament may be immobilized in the passive state include e.g. strong molecular interactions, such as e.g. ionic bonds between a positively or negatively charged form of the medicament and an oppositely charged group or component associated with the drug delivery element 100.
  • strong molecular interactions such as e.g. ionic bonds between a positively or negatively charged form of the medicament and an oppositely charged group or component associated with the drug delivery element 100.
  • independent of the mechanism for mobilization of the medicament in the passive state it is preferred that all such related components are selected, as readily understood in the art, such that effective
  • mobilization is achieved at all temperatures below a first temperature, such as e.g.
  • the medicament is released in a bio-available form, unless hindered to do so due to other factors, e.g. a too low a temperature, as disclosed herein, when becoming wet or moist, i.e. when turned into an active moist state. Hence, the release of medicament from the drug delivery system is water triggered.
  • the medicament is immobilized in the passive dry state by being e.g.
  • the release of medicament in the corresponding active state is dependent on the lowering of the melting or transition point of the solid or semisolid carrier to a liquid form thereof when additional water is present.
  • the lowered melting or transition point i.e. a second temperature
  • the drug delivery system may be further adapted for placement within a bodily cavity and for
  • the drug delivery system may also be further adapted for placement on typically the skin, e.g. in the form of an adhesive plaster or patch, and for administration of medicament thereto, i.e. typically dermally, upon user or condition triggered activation.
  • the drug delivery element 100 essentially comprises a carrier matrix, adapted to provide mechanical stability to and withhold the medicament and other constituents or components, such as e.g. suitable chemicals, essential for the intended function of the drug delivery element 100.
  • the medicament In the dormant passive essentially dry state, the medicament may exist in the form of a solid salt, in a neutral form immobilized in a solid or semisolid suitable pharmaceutically acceptable carrier, in a zwitterionic form
  • the medicament may exist in a bio-available neutral or zwitterionic form, for example as a neutral free base or as a protonated neutral acid.
  • the transition of the dormant into the bio-available form of the medicament is dependent on the presence of water, without which the necessary process cannot occur effectively.
  • Examples of such processes or principles, which form basis for the transition of a dormant form of the medicament into a bio-available or releasable form of the medicament include: (A) the reaction of the salt form of a medicament comprising a basic functionality, e.g. an amine or amidine group, with a stronger or at least comparably strong base present within the drug delivery element 100, (B) the reaction of the salt form of a medicament comprising an acidic functionality, e.g.
  • the liquid carrier may comprise dissolved or dispersed medicament and leak out from the drug delivery element 100, optionally through channels or pores of the outer element 101, such as e.g. channels or pores of a suitable film or sheet mounted in contact with and between the drug delivery element 100 and e.g. the skin of a patient, to reach the site of intended administration.
  • the user or condition controlled administration of medicament depends on and is related to user or condition controlled provision of water to the drug delivery element 100.
  • the provided water may originate from an external source, e.g. from a mucous membrane of the user or in form or sweat or any other aqueous secretion, or from an internal source, e.g. from one or several internal containers 103, residing in e.g. the outer element 101, which may controllably be brought in connection with the drug delivery element 100.
  • Various mechanically based valves and systems for such user or condition, e.g. temperature, controlled connections of the internal container 103 with the drug delivery element 100 is known in the art and the skilled person will easily identify which ones of these may be applied to the present drug delivery system.
  • Exemplary novel and advantageous pressure and temperature sensitive control systems are disclosed herein and illustrated in Figs. 7 to 9 and 11 to 12.
  • the drug delivery system may be used for administration of the medicament to the skin or mucous membranes of a patient.
  • the drug delivery system may be used for administration of the medicament to the female reproductive organs or parts thereof.
  • organs or parts thereof include the vaginal cavity, the cervix and the cervix canal.
  • the drug delivery system may comprise an outer sheet or film, as well known in the art, which is practically impermeable to medicaments, located adjacent to the areas within the vaginal cavity to which no or only a minimal amount of medicament is to be administered.
  • the drug delivery system may comprise an outer non- permeable film located at all areas of its outer surface with exception of the part which is adjacent to the cervix, when placed in the vaginal cavity, for selective administration of medicaments, e.g. local anesthetics, to the cervix and optionally to the cervix canal.
  • the drug delivery system may have an elongated tubular form.
  • Advantages of such an elongated tubular form include optimal delivery of medicament within bodily cavities, such as e.g. the vagina or the mouth.
  • the tubular form shaped drug delivery system may be shaped in a suitable irregular shape to maximize the contact surface within the body cavity in which it is placed.
  • the most forward part of the drug delivery system intended for administration of medicaments, e.g. local anesthetic's, to the cervix when placed in the vaginal cavity may have a larger diameter in comparison to the rest of the elongated drug delivery system.
  • the elongated drug delivery system might further be suitably bent to maximize the contact area with the cervix.
  • the exact shape and dimensions of the drug delivery system is dependent on the bodily cavity in which it is intended for use, and is well known to the skilled person.
  • the drug delivery system may have a shape in the form of a sheet, plaster or patch. It may, advantageously, be provided with one or several adhesive elements to allow fastening on e.g. the skin.
  • the drug delivery system may be shaped in a suitable irregular shape to maximize the contact surface with the body onto which it is placed. The exact shape and dimensions of the drug delivery system is dependent on the bodily surface onto which it is intended for use, and is well known to the skilled person.
  • the drug delivery element 100 or the outer element 101, or suitable parts of any of these elements may be adapted to swell in the presence of water, e.g. when the drug delivery system is brought into the active state.
  • the contact area with the inside of and positioning of the drug delivery system in the body cavity in which it is placed, is thereby advantageously maximized.
  • the contact area with the surface of and positioning of the drug delivery system on the body part onto which it is placed is thereby also advantageously maximized.
  • Suitable medically acceptable materials with such swelling properties are well known to the skilled person.
  • the outer element 101 may be a water and medicament permeable film or sheet with low friction.
  • suitable such films or sheets include outer sheets or films of tampons women use during their menstrual period, which sheets or films are associated with a low friction for improved
  • the carrier matrix may be an essentially water insoluble hydrophilic polysaccharide, such as e.g. a porous or fibrous polysaccharide, or the like.
  • hydrophilic polysaccharide include e.g. cellulose, such as cotton, modified cellulose, or the like.
  • the drug delivery system may comprise a drug delivery element 100, an optional outer element 101, a charged form of one or several medicaments being either a positively charged form, e.g. a protonated positively charged form of a medicament with basic properties, or a negatively charged form, e.g.
  • a de-protonated negatively charged form of a medicament with acidic properties one or several pharmaceutically acceptable counterions with a charge which is opposite the charge of the charged form of one or several medicaments, a pharmaceutically acceptable base, capable of converting the positively charged form of one or several medicaments into a neutral or switterionic form, or a pharmaceutically acceptable acid, capable of converting the negatively charged form of one or several medicaments into a neutral or switterionic form, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be selected from the group consisting of compounds (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), each depicted in Fig. 10, or mixtures thereof.
  • the pharmaceutically acceptable carrier may comprise a mixture of compounds (V), (VII) and/or (VIII) and (IX), each depicted in Fig. 10.
  • a carrier is suitable for administration of medicaments, e.g. local anesthetic's, e.g. to the cervix, due to advantageous thermo gelling properties.
  • the pharmaceutically acceptable carrier may comprise a mixture of compounds (II) and/or (III) and (IV), each depicted in Fig. 10, in which the R-group may be represented by an unsaturated straight carbon chain comprising 15 to 23 carbon atoms and one or two Z-double bonds, such as e.g. the carbon chains of linoleic acid, or preferably oleic acid .
  • Such a carrier is suitable for administration of medicaments, e.g. local anesthetic's, e.g. to the cervix, due to advantageous mucoadhesive properties.
  • the pharmaceutically acceptable carrier may be a singularity or plurality of compounds selected from the group of compounds consisting of compounds of formula (V), (VI), (VII) and (VIII), each depicted in Fig. 10.
  • the compound or the mixture of compounds may preferably be selected such that they exist in a solid or semisolid form in the dormant state, and in a liquid form in the active state, i.e. in the presence of water.
  • the pharmaceutically acceptable carrier may be a hydrophilic compound or mixture of compounds, which is miscible with water in all proportions.
  • This compound or mixture of compounds may, when being employed as carrier in the drug delivery element 100 and when being mixed with other optional components therein, exist as a solid or semisolid in the dormant dry state at a temperature below 25, 30, 35 or preferably below 40 °C.
  • This compound or mixture of compounds may, when exposed to water in the active state at a temperature above 10, 20, 25 or 30 °C, undergo a transition to a liquid state, whereby therein dissolved or dispersed medicament may be released from the drug delivery element 100.
  • Suitable such compounds or mixtures of compounds are well known in the art and include e.g. suitable compounds of formula (V), (VI), (VII) and (VII) depicted in Fig. 10, or the like.
  • the salt form of a medicament comprising a basic functionality may be the salt form generated upon reaction with an acid selected from the group of pharmaceutically acceptable acids consisting of 1 -hydroxys- naphthoic, 2,2-dichloroacetic, 2-hydroxyethanesulfonic, 2-oxoglutaric, 4- acetamidobenzoic, 4-aminosalicylic, acetic, adipic, ascorbic, aspartic, benzenesulfonic, benzoic, camphoric, camphor- 10-sulfonic, capric, caproic, caprylic, carbonic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane- 1,2-disulfonic, ethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic, glucuronic, glutamic, glutaric,
  • acids are suitable for a particular medicament comprising a basic functionality, to give a positively charged form of that medicament suitable for prolonged storage in the dormant state of the drug delivery system of the invention.
  • a positively charged form of a medicament comprising a basic functionality may advantageously be combined with a pharmaceutically acceptable solid or immobilized base in the present drug delivery system.
  • Such base is preferably a strong enough base to generate the neutral form of the medicament in the active wet state, as well known by the skilled person.
  • the base existing in a solid or semisolid form in the dormant state, and employed for the generation of a neutral and bioavailable form of a medicament from a positively charged form of that medicament in the active wet state may be selected from carbonates or hydroxides of the group of elements consisting of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • the salt form of a medicament comprising an acidic functionality may comprise a cation of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or diethanolamine.
  • the acid existing in a solid or semisolid form in the dormant state, and employed for the generation of a neutral and bioavailable form of a medicament from a negatively charged form of that medicament in the active wet state may be selected from pharmaceutically acceptable acids disclosed in other embodiments herein that normally exist in a solid or semisolid form.
  • the drug delivery system may comprise a drug delivery element 100, an optional outer element 101, a positively charged form of one or several medicaments, e.g. a protonated positively charged form of a medicament with basic properties, one or several pharmaceutically acceptable counterions with negative charge, a pharmaceutically acceptable base capable of converting the positively charged form of one or several medicaments into a neutral or zwitterionic form, and optionally a pharmaceutically acceptable carrier.
  • a positively charged form of one or several medicaments e.g. a protonated positively charged form of a medicament with basic properties, one or several pharmaceutically acceptable counterions with negative charge, a pharmaceutically acceptable base capable of converting the positively charged form of one or several medicaments into a neutral or zwitterionic form
  • optionally a pharmaceutically acceptable carrier e.g. a pharmaceutically acceptable carrier.
  • the drug delivery system may comprise a drug delivery element 100, an optional outer element 101, a positively charged form of one or several medicaments, e.g. a protonated positively charged form of a medicament with basic properties, one or several pharmaceutically acceptable counterions with negative charge, a base attached to the drug delivery element 100 by strong molecular interaction or covalent bonding selected from the group consisting of chitosan, polylysine and other types of polymeric amines as known in the art, and optionally a pharmaceutically acceptable carrier.
  • a positively charged form of one or several medicaments e.g. a protonated positively charged form of a medicament with basic properties
  • one or several pharmaceutically acceptable counterions with negative charge e.g. a protonated positively charged form of a medicament with basic properties
  • a pharmaceutically acceptable counterions with negative charge e.g. a protonated positively charged form of a medicament with basic properties
  • a base attached to the drug delivery element 100 by strong molecular interaction or covalent bonding selected from the group consisting
  • the drug delivery system may comprise a drug delivery element 100, an optional outer element 101, one or several protonated positively charged forms of a basic known normally dermally administered drug, e.g. comprising an amine group or any other basic functionality, one or several
  • a pharmaceutically acceptable counterions with negative charge a pharmaceutically acceptable base capable of converting the positively charged form of the one or several known normally dermally administered drugs into a neutral or switterionic form, e.g. a neutral free base, and optionally a pharmaceutically acceptable carrier.
  • the drug delivery system may comprise a drug delivery element 100, an optional outer element 101, a positively charged form of one or several local anesthetics, e.g. a protonated positively charged form of a basic local anesthetic with an amine group or any other basic functionality, one or several pharmaceutically acceptable counterions with negative charge, a pharmaceutically acceptable base capable of converting the positively charged form of the one or several local anesthetics into a neutral or switterionic form, e.g. a neutral free base, and optionally a pharmaceutically acceptable carrier.
  • a positively charged form of one or several local anesthetics e.g. a protonated positively charged form of a basic local anesthetic with an amine group or any other basic functionality
  • one or several pharmaceutically acceptable counterions with negative charge e.g. a pharmaceutically acceptable base capable of converting the positively charged form of the one or several local anesthetics into a neutral or switterionic form, e.g. a neutral free base, and
  • Examples of basic local anestetics include, but is not limited to, trimecaine, ropivacaine, prilocaine, mepivacaine, lidocaine, levobupivacaine, etidocaine, cinchocaine, bupivacaine, articaine, tetracaine, proxymetacaine, procaine, propoxycaine, piperocaine, dimethocaine, cyclomethycaine, cocaine, chloroprocaine, benzocaine and mixtures thereof, such as e.g. mixtures of lidocaine and prilocaine.
  • the drug delivery system may comprise a drug delivery element 100, an optional outer element 101, one or several neutral
  • medicaments e.g. medicaments essentially without basic or acidic properties
  • a pharmaceutically acceptable carrier may preferably exist as a solid or semisolid at a temperature of 30 or 40°C or less when being essentially dry and comprising the one or several neutral medicaments.
  • the pharmaceutically acceptable carrier may preferably exist as a liquid, capable of wetting the outer surface of the drug delivery element 100, at a temperature of e.g. 35°C or more, preferably e.g. 20°C or more or 30°C or more, when comprising the one or several neutral medicaments and more than 5% by weight of water, such as more than 10%, 20%, 30%, 40%, 50%, 75% or 90% by weight of water.
  • Suitable pharmaceutically acceptable carriers include e.g. suitable compounds of formula (V), (VI), (VII) and (VII) depicted in Fig. 10, or the like.
  • medicaments that may be administered dermally or to mucous membranes by employment of the present drug delivery system may have a local pharmacological effect.
  • Such medicaments are well known in the art.
  • medicaments that may be administered dermally or to mucous membranes by employment of the present drug delivery system may have a systemic pharmacological effect.
  • Such medicaments are well known in the art.
  • the drug delivery system may comprise an eutectic mixture comprising at least one pharmaceutically active ingredient, which mixture is having an eutectic point in the moist state at a temperature being less than the second temperature.
  • the first temperature may be a temperature which is higher than normal storage, ambient or room temperature, such as higher than e.g. 25°C or preferably higher than 30°C, more preferred higher than 40°C.
  • the second temperature may be equal to or lower than an internal body temperature at the site of placement of the drug delivery system, such as typically lower than e.g. 37°C, preferably lower than 35 or 30°C.
  • the second temperature may be equal to or lower than an internal body temperature at the site of placement of the drug delivery system and simultaneously higher than normal storage, ambient or room temperature.
  • suitable intervals of the second temperature include 25 to 37°C, more preferred 27 to 35°C and most preferred 28 to 32°C.
  • the second temperature may be equal to or lower than the body temperature, e.g. an internal body temperature, at the site of placement of the drug delivery system and simultaneously higher than normal storage, ambient or room temperature and the first temperature may be a temperature which is higher than normal storage, ambient or room temperature.
  • suitable combinations of the first and the second temperature include (first temperature / second temperature): higher than 30°C / lower than 35°C; higher than 40°C / lower than 30°C; higher than 40°C / 27 to 35°C; and higher than 40°C / 28 to 32°C.
  • Adaption of the drug delivery system allow for optimal long term storage of the same in a dry inactive state, and release of medicament in the active moist state only when applied within a body cavity or on e.g. the skin or on a mucous membrane.
  • the active moist state may be a state which is entered when the drug delivery element 100 exceeds 5, 10, 20, 30, 40, 50, 60, 70 or 80 %, by weight, of water.
  • the drug delivery system may comprise one or several integrated container adapted to contain water or an aqueous solution for enabling provision of water to the drug delivery element 100.
  • the provision of water may be user or condition, e.g. temperature, controlled by the inclusion of one or several pressure sensitive conduits or valves or one or several temperature sensitive and essentially water insoluble plugs, respectively, along the fluid connection between the one or several containers and the drug delivery element 100.
  • the pressure sensitive conduits or valves open(s) to allow fluid transfer from the containers to the drug delivery element 100.
  • the critical temperature is preferably slightly lower than the temperature of the cavity in which, or the surface onto which, the drug delivery system is applied and higher than the storage temperature of the drug delivery system, at which it is stored before use. Examples of ranges of suitable critical temperatures include 30 to 35 °C, 28 to 33 °C or 32 to 37 °C.
  • the drug delivery system may comprise one or several integrated containers adapted to contain water or an aqueous solution for enabling provision of water to the drug delivery element 100.
  • the provision of water may be temperature controlled by the inclusion of one or several temperature sensitive and essentially water insoluble plugs along the fluid connection between the container and the drug delivery element 100.
  • the critical temperature is preferably slightly lower than an abnormally high temperature of the cavity in which, or of the surface onto which, the drug delivery system is applied and higher than the normal temperature of the cavity or surface in/on which the drug delivery system is applied.
  • ranges of suitable critical temperatures include 36 to 38 °C, 37 to 39 °C, 38 to 40 °C or about 38 °C.
  • Advantages of a drug delivery system with such a temperature sensitive plug include automatic delivery of suitable medicaments triggered by an abnormally high temperature which may be a symptom, e.g. fever, of the condition the medicament is intended to be administered to treat or ameliorate.
  • the obtained solid (11.18 g) was then heated to 60 °C while stirring until liquefied (10 minutes) and poured onto a water insoluble hydrophilic carrier matrix in the form of medical cotton (3.14 g).
  • the obtained hot mixture was kneaded while cooling to form an exemplary cotton based drug delivery element 100 of the invention in a passive essentially dry state.
  • each of the tubes were then attached at the male luer- fitting to the female luer-fitting of a respective injection needle, with its needle tip stuck into a hard rubber mat, whereby liquid or gaseous transfer was prevented from the bottom of each of the tubes.
  • Addition of ⁇ -heptane (2.8 to 3.9 ml) through the top opening of each of the tubes then immediately followed.
  • the tubes were divided into two different groups, each group kept at a temperature of 21 to 23 °C (group I) or at a temperature of 36 to 38 °C (group II).
  • the ⁇ -heptane phase of each of the tubes were analyzed by TLC (2 uL applied on silica gel coated 5x10 cm glass-sheets eluted with methylene chloride : methanol 92.5 : 7.5 v : v) at the following time points after water injection: 1, 3 and 6 hours.
  • the concentration of lidocaine was estimated by visual comparison of the intensity of the spots, when visualized under UV (254 nm), with spots of reference solutions of lidocaine and assigned to one of the following categories: ⁇ 2mM (low), 2 to 5 mM (medium) and 5 to 10 mM (high).
  • exemplary drug delivery element 100 releases no or minimal amounts of medicament at a relatively low temperature of 21 to 23 °C, i.e. a normal ambient storage temperature, independent of water content, i.e. independent of existing in an essentially dry or in a moist state. Furthermore, at a relatively high temperature of 36 to 38 °C, i.e. a temperature essentially corresponding to human body temperature, it is shown that release of medicament is positively correlated to the water content, i.e. dependent on the existence in one of an essentially dry state or a moist state.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Anesthesiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un système d'administration de médicament pour une administration de médicament déclenchée par de l'eau. Il comprend un élément d'administration de médicament (100) qui comprend une matrice de support hydrophile essentiellement insoluble dans l'eau, qui est un polysaccharide poreux ou fibreux, et un ensemble d'éléments comprenant le médicament. L'élément d'administration de médicament (100) a un état essentiellement sec passif, dans lequel essentiellement aucune quantité pharmaceutiquement efficace du médicament n'est libérée, et un état humide actif, dans lequel au moins une forme neutre ou zwitterionique du médicament est libérée.
PCT/SE2015/050279 2014-03-13 2015-03-11 Système d'administration de médicament en forme de feuille ou tubulaire WO2015137872A1 (fr)

Applications Claiming Priority (4)

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SE1430036 2014-03-13
SE1430037 2014-03-13
SE1430036-2 2014-03-13
SE1430037-0 2014-03-13

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3629994A1 (de) * 1986-09-03 1988-03-17 Weissenbacher Ernst Rainer Pro Vorrichtung zur medikamentenapplikation in koerperhoehlen bzw. auf koerperoberflaechen
US4738848A (en) * 1985-06-04 1988-04-19 Nitto Electric Industrial Co., Ltd. Anti-inflammatory analgesic adhesive preparation
US4917676A (en) * 1986-11-20 1990-04-17 Ciba-Geigy Corporation User-activated transdermal therapeutic system
US5234957A (en) * 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
WO2004064811A1 (fr) * 2003-01-24 2004-08-05 Magle Holding Ab Matiere de composition pour administration a travers la muqueuse
US7175853B1 (en) * 1998-03-30 2007-02-13 Lts Lohmann Therapie-Systeme Ag Therapeutic system which can be moisture-activated

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4738848A (en) * 1985-06-04 1988-04-19 Nitto Electric Industrial Co., Ltd. Anti-inflammatory analgesic adhesive preparation
DE3629994A1 (de) * 1986-09-03 1988-03-17 Weissenbacher Ernst Rainer Pro Vorrichtung zur medikamentenapplikation in koerperhoehlen bzw. auf koerperoberflaechen
US4917676A (en) * 1986-11-20 1990-04-17 Ciba-Geigy Corporation User-activated transdermal therapeutic system
US5234957A (en) * 1991-02-27 1993-08-10 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US7175853B1 (en) * 1998-03-30 2007-02-13 Lts Lohmann Therapie-Systeme Ag Therapeutic system which can be moisture-activated
WO2004064811A1 (fr) * 2003-01-24 2004-08-05 Magle Holding Ab Matiere de composition pour administration a travers la muqueuse

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