WO2019141178A1 - 药物组合物、贴剂及其制备方法、镇痛方法、应用 - Google Patents

药物组合物、贴剂及其制备方法、镇痛方法、应用 Download PDF

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Publication number
WO2019141178A1
WO2019141178A1 PCT/CN2019/071898 CN2019071898W WO2019141178A1 WO 2019141178 A1 WO2019141178 A1 WO 2019141178A1 CN 2019071898 W CN2019071898 W CN 2019071898W WO 2019141178 A1 WO2019141178 A1 WO 2019141178A1
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Prior art keywords
pain
skin
pharmaceutical composition
active ingredient
hours
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PCT/CN2019/071898
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English (en)
French (fr)
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张洁
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张洁
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Application filed by 张洁 filed Critical 张洁
Priority to EP19741485.7A priority Critical patent/EP3741364A4/en
Priority to US16/962,414 priority patent/US20210023018A1/en
Priority to CN201980008813.6A priority patent/CN111615383A/zh
Publication of WO2019141178A1 publication Critical patent/WO2019141178A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
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Definitions

  • the invention relates to a pharmaceutical composition, a patch, a preparation method thereof, an analgesic method and application.
  • Local anesthetic preparations are used to prevent or treat pain in the skin or mucous membranes, for example: 2% lidocaine hydrochloride gel is used to relieve pain associated with sunburn; Enna (English name EMLA) is a type containing lidocaine An emulsion of low-point co-melting oil droplets with prilocaine for anesthesia of intact skin with pain prior to surgery; Lidoderm is a cured gel patch containing 5% lidocaine for reducing banding Postherpetic neuralgia (the skin itself is intact); Pliaglis is an emulsion containing 7% lidocaine and 7% tetracaine low-point eutectic oil droplets for use in pre-operative intact skin with pain Anesthesia.
  • each of the above local anesthetics has serious limitations.
  • lidocaine hydrochloride gel can not anesthetize intact skin; prilocaine in EMLA can cause methemoglobinemia; tetracaine in Pliaglis can cause allergic reactions related to ester local anesthetics, and tetracaine will be Hydrolysis, so Pliaglis must be stored refrigerated to reduce the rate of hydrolysis; Lidoderm can not anesthetize intact skin within 120 minutes or even 4 hours, and Lidoderm can not be used for more than 12 hours each time.
  • the common limitation of each of the above-mentioned local anesthetic preparations is that a long-term continuous safe analgesic effect cannot be achieved.
  • the ideal product is a continuous analgesic effect of 12, 18, 24, or even 30 hours. Therefore, the search for a pharmaceutical composition having a long-term continuous safe analgesic effect is an urgent problem to be solved.
  • the formula layer is usually applied to the affected area, and then covered with a medical film. During the analgesia, the formula layer is squeezed by external force, which causes the formula layer of the affected area to become thinner, thereby greatly shortening the effective analgesic time. . Therefore, the search for a patch capable of ensuring the thickness of the formulation layer is also an urgent problem to be solved.
  • the technical problem to be solved by the present invention is to overcome the defects that the local anesthetic preparation in the prior art has the common limitation that the long-term continuous safe analgesic effect cannot be achieved, and the pharmaceutical composition, the patch and the preparation method thereof are provided. , analgesic methods, applications.
  • the pharmaceutical composition and the patch can obtain a continuous safe analgesic effect of 12, 18, 24, or even 30 hours, and the patch can resist the extrusion of a certain external force, and can protect the covered coating layer from being squeezed away, thereby maintaining The thickness of the formulation layer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a single anesthetic active ingredient comprising an anesthetic active ingredient dissolved in water and an anesthetic active ingredient in an undissolved state; the anesthetic active ingredient
  • the mass percentage in the pharmaceutical composition is 2% or more; the mass percentage of the anesthetic active ingredient dissolved in water in the pharmaceutical composition is 1% or less; and the anesthetic active ingredient is lidocaine and butyl Cain, bupivacaine, atucaine, cocaine, dibucaine, eticacaine, levobupivacaine, mepivacaine, prilocaine, ropivacaine, tricainine, Benzocaine or procaine.
  • the pharmaceutical composition of the present invention is capable of achieving a continuous analgesic effect of 12, 18, 24, or even 30 hours (for example, a patient who has pain in the incision after surgery provides an analgesic effect for more than 24 hours at the incisional wound; for herpes zoster Patients with post-neural pain provide an analgesic effect of 12 hours or more on the sore skin).
  • the preparation in the context of the invention, the "formulation" refers to the pharmaceutical composition of the present invention
  • Lidocaine has a better advantage as a single anesthetic active ingredient than the pharmaceutical composition of the present invention and the marketed product (products containing two or more local anesthetic ingredients, such as Enna): (1) The preparation is safer, easier to approve, and can be used for a long time (can be used continuously for more than three months).
  • 1 lidocaine is the most commonly used local anesthetic, and its safety is generally known; Formulations are more likely to be approved for use by the relevant government authorities (such as the Food and Drug Administration of China and the United States); 3 lidocaine is the only local anesthetic approved by the US Food and Drug Administration for long-term use (typically more than three months) (For many diseases that require long-term analgesia, it is important to be able to approve long-term use, for example, in analgesic applications for post-herpetic neuralgia, patients may need to use analgesic preparations for many years, if a preparation contains The local anesthetic is not lidocaine.
  • the agent can anesthetize intact skin within 120 minutes or even 90 minutes. Specifically, the ability to anesthetize intact skin within 90 minutes or 120 minutes is also very important, because the patient's pain is relieved in time, especially herpes zoster. Pain like post-neural pain is important to the patient; (3)
  • the formulation can also be used for analgesia of non-intact skin (eg, post-operative incisional wounds and analgesia with herpes zoster pain).
  • the mass percentage of the anesthetic active ingredient in the pharmaceutical composition may be 3% or more, 4% or more, 5% or more, 8% or more, or 10% or more, for example, 3% to 15%. 4%-10% or 5%-8%.
  • the mass percentage of the anesthetic active ingredient dissolved in water in the pharmaceutical composition may be 0.7% or less, 0.5% to 0.7% or 0.5% or less.
  • the granules of the anesthetic active ingredient may be granules of an anesthetic active ingredient conventionally used in the art, and preferably, more than 80% of the granules of the anesthetic active ingredient have a single weight of 0.01 to 10 mg.
  • the pharmaceutical composition preferably includes a thickening agent, and the addition of the thickening agent can increase the viscosity of the preparation and prevent the application of the coating on the skin from flowing out of the skin of the target area.
  • the thickener is preferably one or more of starch, carbomer and cellulose, more preferably one or more of starch, hydroxyethyl cellulose and hydroxypropyl cellulose.
  • the mass percentage of the thickener in the pharmaceutical composition is preferably from 0.02% to 4%, more preferably from 0.02% to 2%, still more preferably from 0.02% to 1%.
  • the pharmaceutical composition preferably includes glycerin and/or propylene glycol, and the addition of glycerin and/or propylene glycol can reduce the risk of irritating the skin.
  • the mass percentage of the glycerin and/or propylene glycol in the pharmaceutical composition is preferably from 2% to 25%.
  • the pharmaceutical composition preferably comprises a suspending agent, which may be a suspending agent conventionally used in the art, and the suspending agent is preferably a carbomer, and the suspending agent is preferably of a preferred type.
  • the site is Pemulen TR-2 and the manufacturer is Lubrizol.
  • the mass percentage of the suspending agent in the pharmaceutical composition is preferably from 0.10% to 0.50%.
  • the pharmaceutical composition may have a pH of 7 or more or 8 or more, and may be, for example, 7-13, 7-11 or 7.5-9.5.
  • the pH of the pharmaceutical composition can be adjusted to the above pH range by using a pH adjusting agent conventionally used in the art, for example, one of sodium tripolyphosphate, sodium hydrogencarbonate, sodium hydroxide and potassium hydroxide can be used. Or more; preferably sodium hydroxide and/or potassium hydroxide. More preferably, sodium hydroxide is used.
  • the mass ratio of the sodium hydroxide to the Pemulen TR-2 is 9:16 or more.
  • the mass percentage of the tetracaine in the pharmaceutical composition is 0.5% or more, and the tetracaine dissolved in water is The mass percentage in the pharmaceutical composition is 0.1% or less.
  • the present invention also provides a process for the preparation of the aforementioned pharmaceutical composition, which comprises the steps of mixing the components of the pharmaceutical composition.
  • the preparation method comprises the steps of: (1) mixing the remaining components of the pharmaceutical composition other than the anesthetic active ingredient to obtain a mixed solution; (2) mixing the mixed liquid The anesthetic active ingredient is heated and then cooled to room temperature.
  • the heating temperature is preferably from 75 to 85 ° C, for example, 80 ° C.
  • the heating is preferably carried out under stirring.
  • the present invention also provides a patch comprising a cover film and the aforementioned pharmaceutical composition, the contact surface of the cover film with the skin is provided with at least one recess, and the area of the opening of the recess occupies the contact surface More than 70% of the total area, but not including 100%, the depression is filled with the pharmaceutical composition.
  • the cover film may be made of a variety of materials or combinations of materials, generally a soft but not easily crushed material, optionally a foamed plastic such as polyurethane.
  • the cover film has a certain structure and hardness, and the cover film is further provided with a concave structure.
  • the formulation in the concave structure is not easily squeezed away from the affected part.
  • the cover film preferably has a water vapor permeability of from 100 to 10,000 g/m 2 /24 hours, more preferably from 400 to 4000 g/m 2 /24 hours.
  • the water vapor permeability (in English, referred to as the moisture vapor transmission rate, abbreviated as MVTR) is measured according to a common method in the industry.
  • MVTR moisture vapor transmission rate
  • the thickness of the cover film is preferably from 1 to 20 mm, more preferably from 3 to 10 mm.
  • the length of the cover film is preferably from 3 to 50 cm, more preferably from 8 to 30 cm.
  • the area of the cover film is preferably from 5 to 1000 square centimeters, more preferably from 10 to 500 square centimeters.
  • the configuration of the recess is preferably one or more of a rectangular parallelepiped, a cylinder, and a hemisphere. More preferably, the axis of the cylinder is perpendicular to the contact surface, the axis of the hemisphere being perpendicular to the contact surface. Further preferably, the depressions are configured as hemispheres, and the openings of each of the depressions are tangential to the openings of the adjacent depressions.
  • the depth of the depression may be 10 mm or less, preferably 0.2 to 10 mm, more preferably 0.5 to 3 mm.
  • the cover film may be provided with only one recess, the recess having a recessed cavity, the recess having an opening width of preferably 2-40 mm, more preferably 3-20 mm;
  • the opening length is preferably from 2 to 50 cm, more preferably from 5 to 20 cm.
  • the cover film may further be provided with two or more depressions, and the number of the depressions per square centimeter of the cover film is preferably from 0.2 to 100, more preferably from 0.5 to 20;
  • the spacing between two adjacent recesses is preferably from 0 to 5 mm, more preferably from 0 to 2 mm. Further preferably, the two adjacent recesses are not in communication.
  • the cover film is provided with only one recess, the recess has a recessed cavity, and the contact surface of the recessed cavity and the skin is provided with a plurality of first through holes, and the recessed cavity includes a layer or a layer
  • each of the drug storage chamber units includes a plurality of micro drug storage chambers, and a sidewall of each of the micro drug storage chambers is provided with a second through hole, and the second through hole is used for the communication phase
  • Two micro-reservoir chambers are adjacent to each other; the opening area of the first through-hole accounts for more than 70% of the total area of the first surface, but does not include 100%.
  • all of the micro-reservoir chambers form a network structure of loofah.
  • the micro-reservoir chamber is a cavity having a shape of a regular hexagonal prism, and the micro-reservoir chamber is arranged in a honeycomb structure.
  • the micro-reservoir chambers of two adjacent layers are also staggered.
  • the remaining surface of the recessed cavity except the first surface is a closed structure.
  • the depth of the recess is preferably equal to the thickness of the cover film.
  • a side of the recess away from the opening may be partially attached with a barrier film.
  • the side of the recess away from the opening may be entirely attached with a barrier film.
  • the formed cover film is a cover combination.
  • the depth of the recess is equal to the thickness of the cover film for the convenience of processing and manufacturing.
  • the moisture in the formulation layer that has been applied to the skin, wound or mucosa must be maintained during use.
  • One of the methods of retaining moisture is to attach a barrier film, such as a plastic film or a polyurethane film, to the side of the recess away from the opening to form a cover combination, and then cover the cover layer with the cover layer. If the formulation layer is applied to a wound that will exude bodily fluids, then the side of the recess away from the opening may be without a barrier film or partially attached to the barrier film.
  • the recesses have the same configuration, and the recesses are evenly arranged or arranged in an array.
  • the depression in the cover film is filled with the pharmaceutical composition, and the opening is in direct contact with the affected part.
  • the area of the opening is the area in which the pharmaceutical composition directly contacts the affected part.
  • the outer edge of the opening may be a continuous closed curve, which may be a plurality of tangent closed curves, may be a closed curve with only one intersection point, or may be a closed curve with no intersection points.
  • the pitch refers to the minimum distance between the outer edges of two adjacent openings.
  • the present invention also provides a pharmaceutical composition as described above for the treatment of herpes zoster herpes pain, post-herpetic neuropathic pain, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain , pain caused by back pain, gout, pain caused by soft tissue damage, pain after surgery, pain in burns, or pain in burns.
  • the present invention also provides a patch prepared according to the above-mentioned patch for treating herpes zoster herpes pain, post-herpetic nerve damage pain, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain, Application in back pain, pain caused by gout, pain caused by soft tissue damage, post-operative incision pain, burn pain, or pain in burns.
  • the present invention also provides an analgesic method using the aforementioned pharmaceutical composition, the analgesic method comprising the steps of: applying the pharmaceutical composition to the skin of the affected area, and then covering the pharmaceutical composition with a barrier film. .
  • the skin of the affected part may be, for example, the skin of the herpes zoster, the skin of the herpes, the skin of the postherpetic nerve, the skin of the pain, the skin of the neuroma, the skin of the phantom limb, the skin of the diabetic peripheral nerve, the joint pain.
  • the time for holding the pharmaceutical composition on the skin of the affected part is preferably 8 hours or longer, 12 hours or longer, 18 hours or longer, 24 hours or longer, or 30 hours or longer.
  • the thickness of the skin of the drug composition at the affected part is preferably not less than 0.5 mm, not less than 1 mm or not less than 2 mm.
  • the present invention also provides an analgesic method using the aforementioned patch, the analgesic method comprising the steps of: contacting the recessed opening in the patch with the skin of the affected part.
  • the skin of the affected part may be, for example, the skin of the herpes zoster, the skin of the herpes, the skin of the postherpetic nerve, the skin of the pain, the skin of the neuroma, the skin of the phantom limb, the skin of the diabetic peripheral nerve, the joint pain.
  • the time during which the patch is held on the skin of the affected part is preferably 8 hours or longer, 12 hours or longer, 18 hours or longer, 24 hours or longer, or 30 hours or longer.
  • the thickness of the skin of the pharmaceutical composition in the patch to be maintained in the patch is preferably not less than 0.5 mm, not less than 1 mm or not less than 2 mm.
  • intact skin or intact normal human skin means that the main barrier to the foreign body (the stratum corneum) is intact skin.
  • the percentage refers to the mass percentage unless otherwise specified.
  • the phrase "capable of anesthetizing intact normal human skin within 120 minutes” means that most of the human skin will be anesthetized within the time period after administration of the pharmaceutical composition at normal room temperature, from medicine It will be understood by those skilled in the art that the description of such words does not necessarily mean that each individual's skin will be anesthetized within said time.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the present invention is that the present invention provides a pharmaceutical composition, a patch, a preparation method thereof, an analgesic method, and application.
  • the preparation and the patch can obtain a continuous safe analgesic effect for 12, 18, 24, or even 30 hours, and the patch can resist the extrusion of a certain external force, and can protect the covered coating layer from being squeezed away, thereby maintaining the formulation layer. thickness of.
  • the preparation can be used for herpes zoster herpes pain, post-herpetic neuropathic pain, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, joint pain, osteoarthritis pain, back pain, pain caused by gout, Pain caused by soft tissue injury, pain after surgery, pain in burns, or pain during burns.
  • lidocaine Compared with other pharmaceutical compositions of the present invention and other pharmaceutical compositions on the market (products containing two or more local anesthetic active ingredients, such as Enna), lidocaine has a better formulation as a single anesthetic active ingredient.
  • Fig. 1 is a view showing the structure of a cover film and a barrier film of the patch of Example 27.
  • Example 2 is a schematic view showing the structure of a cover assembly of the patch of Example 27.
  • FIG 3 is a schematic view showing the structure of a cover film and a barrier film of the patch of Examples 28 and 32-36.
  • FIG. 4 is a schematic view showing the structure of a cover assembly of the patches of Examples 28 and 32-36.
  • Figure 5 is a schematic view showing the structure of a cover film and a barrier film of the patch of Examples 29-31.
  • Figure 6 is a schematic view showing the structure of the covering combination of the patches of Examples 29-31.
  • Figure 7 is a schematic view showing the structure of a cover film and a barrier film of the patches of Examples 37-41.
  • Figure 8 is a schematic view showing the structure of the covering combination of the patches of Examples 37-41.
  • Fig. 9 is a view showing the structure of a cover film and a barrier film of the patch of Example 42;
  • Fig. 10 is a view showing the structure of a cover assembly of the patch of Example 42.
  • Figure 11 is a schematic view showing the structure of a cover film of the patch of Examples 43-46.
  • Figure 12 is a schematic view showing the structure of the cover assembly of the patches of Examples 43-46.
  • Examples 1 to 24 among the particles of the anesthetic active ingredient, 80% or more of the particles of the anesthetic active ingredient had a single weight of 0.01 to 10 mg.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition is prepared as follows:
  • the obtained pharmaceutical composition is referred to as Formulation A, and the obtained pharmaceutical composition is a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein undissolved lidocaine is present in the form of suspended crystals.
  • the pH of the resulting pharmaceutical composition is higher than 8; 40 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine, and about 35 mg is undissolved suspended lidocaine Because of the crystal.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition is prepared as follows:
  • the obtained pharmaceutical composition is referred to as Formulation B, and the obtained pharmaceutical composition is a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein undissolved lidocaine exists in the form of suspended crystals.
  • the pH of the resulting pharmaceutical composition is higher than 8; a total of 50 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine, and about 45 mg is undissolved suspended lidocaine Because of the crystal.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition is prepared as follows:
  • the obtained pharmaceutical composition is referred to as Formulation C, and the obtained pharmaceutical composition is a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein undissolved lidocaine is present in the form of suspended crystals.
  • the pH of the resulting pharmaceutical composition is above 8; most of the lidocaine is in the form of undissolved suspended crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition was prepared in the same manner as in Example 2.
  • the obtained pharmaceutical composition is referred to as Formulation D, and the obtained pharmaceutical composition is a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein undissolved lidocaine is present in the form of suspended crystals.
  • the pH of the resulting pharmaceutical composition is higher than 8; 100 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine, and about 95 mg is undissolved suspended lidoca Because of the crystal.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition was prepared in the same manner as in Example 2.
  • the obtained pharmaceutical composition is referred to as Formulation E, and the obtained pharmaceutical composition is a viscous solution containing dissolved lidocaine and undissolved lidocaine, wherein undissolved lidocaine is present in the form of suspended crystals.
  • the pH of the resulting pharmaceutical composition is higher than 8; a total of 150 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine, and about 145 mg is undissolved suspended lidocaine Because of the crystal.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition is prepared as follows:
  • the obtained pharmaceutical composition is referred to as Formula F, and less than a quarter of the total amount of bupivacaine of the obtained pharmaceutical composition is dissolved, and the rest are in the form of granules, that is, dissolved cloth.
  • the mass fraction of the bicaine is less than 1%, which is the percentage of the mass of the dissolved bupivacaine to the total mass of the resulting pharmaceutical composition.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition is prepared as follows:
  • the obtained pharmaceutical composition is referred to as Formula G, and less than one tenth of the total amount of tetracaine in the obtained pharmaceutical composition is dissolved, and the rest are in the form of granules, that is, dissolved Dingka
  • the mass fraction is less than 0.4%, which is the percentage of the mass of the dissolved tetracaine to the total mass of the resulting pharmaceutical composition.
  • Example 1 The anesthetic active ingredients in Example 1 were respectively treated with ardivacaine, octicocaine, dibucaine, eticacaine, levobupivacaine, mepivacaine, prilocaine, ropivacaine, and topaz.
  • Examples 8-18 were obtained by replacing cain, benzocaine, and procaine.
  • the obtained pharmaceutical composition is a viscous solution containing a dissolved anesthetic active ingredient and an undissolved anesthetic active ingredient, wherein the undissolved anesthetic active ingredient is present in the viscous solution in the form of suspended crystals;
  • the resulting pharmaceutical composition The pH is above 8; a total of 40 mg of anesthetic active ingredient per ml of solution, wherein: about 5 mg is dissolved and about 35 mg is undissolved suspended crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the pharmaceutical composition is prepared as follows:
  • the pH of the obtained pharmaceutical composition is higher than 8; a total of 20 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine, and about 15 mg is undissolved suspended lidocaine crystal .
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 1.
  • the resulting pharmaceutical composition has a pH above 8; a total of 30 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine and about 25 mg is undissolved suspended lidocaine crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 3.
  • the resulting pharmaceutical composition has a pH above 8; a total of 80 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine and about 75 mg is undissolved suspended lidocaine crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 3.
  • the resulting pharmaceutical composition has a pH above 8; a total of 150 mg of lidocaine per ml of solution, wherein: about 5 mg is dissolved lidocaine and about 145 mg is undissolved suspended lidocaine crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 2.
  • the resulting pharmaceutical composition has a pH above 8; a total of 100 mg of lidocaine per ml of solution, wherein: about 7 mg is dissolved lidocaine and about 93 mg is undissolved suspended lidocaine crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 1, except that the anesthetic active ingredient was tetracaine.
  • the resulting pharmaceutical composition has a pH above 8; a total of 5 mg of tetracaine per ml of solution, wherein: about 1 mg is dissolved tetracaine and about 4 mg is undissolved suspended tetracaine crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 1.
  • the resulting pharmaceutical composition has a pH above 8; a total of 100 mg of lidocaine per ml of solution, wherein: about 7 mg is dissolved lidocaine and about 93 mg is undissolved suspended lidocaine crystals.
  • a raw material composition of a pharmaceutical composition the composition of which is shown in the following table:
  • the preparation method was the same as in Example 1.
  • the resulting pharmaceutical composition has a pH above 8; a total of 100 mg of lidocaine per ml of solution, wherein: about 7 mg is dissolved lidocaine and about 93 mg is undissolved suspended lidocaine crystals.
  • a patch comprising a cover film as shown in FIG. 1 and a formulation D, the cover film being a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours, a thickness of 3 mm, and a length It is 10 cm and has an area of 15 square centimeters.
  • the contact surface of the cover film and the skin is provided with a plurality of depressions 1 which are configured as a rectangular parallelepiped and arranged in an array.
  • the number of depressions per square centimeter of the cover film is 0.8, and the depth of each depression is It is 3 mm, the spacing between two adjacent depressions is 2 mm, and the opening area of the depression accounts for 70% of the total area of the contact surface.
  • the barrier film 2 is also attached to the side of the recess away from the opening, thereby forming the cover combination shown in Fig. 2.
  • the barrier film 2 is a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours. The formulation fills the depression.
  • FIG. 3 The structure of the cover film and the barrier film of Embodiment 28 is shown in FIG. 3, and the cover combination formed is as shown in FIG.
  • FIG. 5 The structural schematic diagrams of the cover film and the barrier film of Examples 29-31 are shown in FIG. 5, and the cover combination formed is as shown in FIG. 6.
  • a patch comprising a cover film as shown in FIG. 3 and a formulation D, the cover film being a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours.
  • the contact surface of the cover film with the skin is provided with a recess 1 which is configured as a rectangular parallelepiped, the depth of the recess 1 is 3 mm, the opening width of the recess 1 is 15 mm, and the opening length of the recess 1 is 5 cm, the recess 1 The opening area accounts for 70% of the total area of the contact surface.
  • the barrier film 2 is also attached to the side of the recess 1 away from the opening, thereby forming a cover combination as shown in FIG. 4.
  • the barrier film 2 is a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours. .
  • the formulation D fills the depression.
  • a patch comprising a cover film as shown in FIG. 7 and a formulation D, the cover film being a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours, a thickness of 3 mm, and a length. It is 10 cm and has an area of 15 square centimeters.
  • the contact surface of the cover film and the skin is provided with a plurality of recesses 1 , the recess 1 is configured as a hemisphere, the height of the hemisphere is perpendicular to the contact surface, and the depression is evenly distributed, and the number of depressions per square centimeter of the cover film is 0.8, the height of each hemisphere depression is 3 mm, the opening area of the depression 1 accounts for 70% of the total area of the contact surface, and the outer edges of the bottom surfaces of the adjacent two hemispheres are tangent.
  • the barrier film 2 is also attached to the side of the recess 1 away from the opening, thereby forming the cover combination shown in FIG. 8.
  • the barrier film 2 is a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours. .
  • the formulation D fills the depression.
  • a patch comprising a cover film as shown in FIG. 9 and a formulation D, the cover film being a polyurethane film having a water vapor permeability of 100 g/m 2 /24 hours, a thickness of 3 mm, and a length. It is 10 cm and has an area of 15 square centimeters.
  • the cover film is provided with only one recess 1 having a recessed cavity and an adhesive layer 3 surrounding the recessed cavity, the recessed cavity having a depth of 3 mm, the recessed cavity having a first surface in contact with the skin, the first The surface is provided with a plurality of first through holes, the first through holes having an opening area of 70% of the total area of the first surface.
  • the recessed cavity includes more than one layer of drug storage chamber unit, and each of the drug storage chamber units includes a plurality of micro drug storage chambers, and a sidewall of each of the micro drug storage chambers is provided with a second through hole (not shown) Marked), the second through hole is used to connect two adjacent micro reservoirs. All micro-reservoir chambers form a network structure of loofah.
  • the cover film is further provided with a barrier film 2 on the side away from the first through hole, thereby forming a cover combination as shown in FIG. 10.
  • the barrier film 2 is a polyurethane film having a water vapor permeability of 100 g/m. 2 / 24 hours.
  • the formulation D fills the depression.
  • the cover film shown in Fig. 11 was a polyurethane film having a water vapor permeability of 400 g/m 2 /24 hours, a thickness of 0.2 mm, a length of 3 cm, and an area of 5 cm 2 .
  • the cover film is provided with only one recess 1 having a recessed cavity and an adhesive layer 3 surrounding the recessed cavity, the recessed cavity having a depth of 0.2 mm, the recessed cavity having a first surface in contact with the skin, the first The surface is provided with a plurality of first through holes, the first through holes having an opening area of 70% of the total area of the first surface.
  • the recessed cavity includes more than one layer of drug storage chamber unit, and each of the drug storage chamber units includes a plurality of micro drug storage chambers, and a sidewall of each of the micro drug storage chambers is provided with a second through hole (not shown) Marked), the second through hole is used to connect two adjacent micro reservoirs.
  • the micro-reservoir chamber is a cavity having a shape of a regular hexagonal prism and arranged in a honeycomb structure, and the micro-reservoir chambers of two adjacent layers are also alternately arranged.
  • the cover film is further provided with a barrier film 2 on the side away from the first through hole, thereby forming a cover combination as shown in FIG. 12, the barrier film 2 being a polyurethane film having a water vapor permeability of 400 g/m. 2 / 24 hours.
  • the formulation D fills the depression.
  • a layer of 2 mm thick Formulation A was applied to a piece of non-woven fabric, and a portion of Formulation A was absorbed into the nonwoven fabric.
  • This nonwoven fabric, which absorbed Formulation A was placed on the skin of the upper arm of a human subject and covered with a layer of impervious plastic film. The plastic film is fixed to the skin by a film.
  • the skin covered by Formulation A was anesthetized after about 90 minutes. Formulation A was removed from the skin 24 hours after the start of administration. The skin covered by Formulation A was still anesthetized when Formulation A was removed and after one hour.
  • a patient's back skin has been suffering from herpes zoster neuralgia for more than 6 years.
  • a layer of Formulation B approximately 1 mm thick, was applied to the affected area and covered with a layer of airtight plastic film.
  • the plastic film is fixed to the skin with a film.
  • the plastic film is designed to prevent evaporation of moisture from the formulation.
  • the patient maintained the formula and plastic film on the skin for 18 hours and then removed them.
  • the patient had a substantially painless time of nearly 20 hours: several hours after the termination of administration 90 minutes after the start of administration. This very satisfying analgesic effect is better than any medicine she has used in the past 6 years, and she has a good night's sleep.
  • she Over the next few months, she repeatedly used Formulation B and other formulations of the Examples, including Formulation C, in the same manner, and achieved similar satisfactory results.
  • the affected area is very painful and red and swollen.
  • a formulation of about 1 mm thick was placed over the affected skin and covered with a layer of plastic film to prevent evaporation of moisture from the formulation.
  • the formulation and plastic film were kept on the skin for 25 hours. Except for the first hour, the patient barely felt pain during these 25 hours. After the formula is removed, the redness and swelling of the affected area is greatly reduced.
  • the patient used Formulation C in a similar manner.
  • the thickness of the skin covered by Formula C this time is about 2 mm.
  • the patient removed the formulation and plastic film after 35 hours. Except for the first hour, the patient received a very satisfactory analgesic effect during these 35 hours.
  • a formulation C of about 2 mm thickness was placed over the affected skin and covered with a layer of plastic film. After an hour, the patient's pain began to decrease significantly. The formulation and plastic film were removed on the skin for 36 hours. In addition to the first hour, the analgesic effect was very satisfactory during these 36 hours.
  • the medical staff In order to relieve the pain of a surgical incision in a caesarean section, the medical staff covered a 3 mm thick, 1.5 cm wide formula D over the sutured surgical incision and covered the formula D with the overlay combination shown in FIG.
  • the lidocaine molecule in the formulation immediately began to penetrate into the incision and surrounding tissue.
  • the patient's surgical incision pain began to be significantly relieved within 15 minutes. Satisfactory analgesic effect lasted for more than 12 hours.
  • the medical staff removes the formula D and the cover combination, and then uses the formula D and the cover combination again using the same operation method. Later, whenever the patient has an analgesic need, the health care provider uses the same method of operation using the Formulation D and coverage combinations.
  • the medical staff covered a 3 mm thick formula F over the sutured surgical incision and covered the formula F with the overlay combination shown in FIG.
  • the bupivacaine molecule in the formulation immediately began to penetrate into the incision and surrounding tissue.
  • the patient's surgical incision pain began to be significantly relieved within 15 minutes. Satisfactory analgesic effect lasted for more than 12 hours. Later, whenever the patient has an analgesic need, the health care provider uses the same method of operation and the combination of coverage and coverage.
  • the medical staff In order to alleviate the pain of a surgical incision in a patient with appendicitis, the medical staff covered a 3 mm thick formula G over the sutured surgical incision and covered the formula G with a medical film.
  • the tetracaine molecules in the formulation immediately began to penetrate into the incision and surrounding tissue.
  • the patient's surgical incision pain began to be significantly relieved within 10 minutes. Satisfactory analgesic effect lasted for more than 24 hours. Later, whenever the patient has an analgesic need, the medical staff uses the same method of operation G and medical film.
  • a patient has pain in the shoulders of the shoulder.
  • a layer 1-2 of a 1-2 mm thick layer was applied to the skin of the shoulder of the patient and covered with the cover combination shown in FIG. After an hour, the pain in the patient's shoulders basically disappeared. This satisfactory analgesic effect lasted for 8 hours on one shoulder joint and the other shoulder joint lasted for more than 18 hours.
  • Formulation A is applied to a layer of gauze that has been covered on a person's burn wound.
  • This formula penetrates the wound through gauze and delivers lidocaine into the wound tissue, which greatly reduces the pain on the wound.
  • This analgesic effect lasts for many hours because of the sustained release of the formula.
  • the formulation layer is directly applied to the burn wound surface, and covered with a cover film as shown in Fig. 6, and the evaporation rate of water in the formulation is lowered, thereby prolonging the effective analgesic time.
  • the pain caused during the debridement of the wound surface is covered with a coating film as shown in Fig. 6 on the layer of the coating which has been applied to the gauze, and the evaporation rate of water in the formulation is lowered, thereby prolonging the effective analgesic time.
  • a patient's knee has pain caused by osteoarthritis.
  • a layer of Formula C approximately 2 mm thick was applied to the skin of the entire knee joint and covered with a cover assembly as shown in FIG. The patient took the formula off the knee for 18 hours and removed the same procedure every day. The patient's pain is therefore greatly reduced.
  • a patient's ankle has pain from gout.
  • a layer of Formula C approximately 2 mm thick was applied to the skin of the entire ankle joint and covered with a cover combination as shown in FIG. The patient took the formula off the ankle for 18 hours and removed the same procedure daily. The patient's pain is therefore greatly reduced.
  • a 2 mm thick pharmaceutical composition of Examples 8-26 was applied to a nonwoven fabric, and a part of the formulation was absorbed into the nonwoven fabric.
  • This non-woven fabric that absorbed the formula was placed on the skin of the upper arm of a human subject and covered with a layer of impervious plastic film. The plastic film is fixed to the skin by a film.
  • the skin covered by the formula was anesthetized after about 90 minutes.
  • the formulation was removed from the skin 24 hours after the start of administration.
  • the skin covered by the formula is still anesthetized when the formula is removed and after one hour.
  • the medical staff covered the patch described in Examples 27-46 on the surgical incision after suturing.
  • the lidocaine molecule in the formulation immediately began to penetrate into the incision and surrounding tissue.
  • the patient's surgical incision pain began to be significantly relieved within 15 minutes.
  • analgesia the patient is accompanied by daily movements such as turning over and lying on the side.
  • the cover film plays a good role in resisting external force extrusion to protect the covered coating layer from being squeezed away, and always maintains the thickness of the formulation layer.
  • the analgesic effect lasted for more than 12 hours.
  • the medical staff uses the same method of application D and the cover combination.
  • the cover film plays a good role in resisting the external force to protect the covered formula. The layer is not squeezed away and the thickness of the formulation layer is always maintained.
  • the pharmaceutical compositions of Examples 1-26 were used for herpes zoster pain, herpes zoster neuralgia, neuroma pain, phantom limb pain, diabetic peripheral neuralgia, arthralgia including osteoarthritis pain , soft tissue injury, gout, surgical incision pain, burning pain or pain when burned to remove phlegm, the pharmaceutical composition can have a continuous analgesic effect of 12-30 hours.

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Abstract

本发明公开一种药物组合物、贴剂及其制备方法、镇痛方法、应用。该药物组合物包括单一的麻醉活性成分，麻醉活性成分包括溶解于水的麻醉活性成分和以未溶解状态存在的麻醉活性成分；麻醉活性成分在药物组合物中的质量百分比为2％以上；溶解于水的麻醉活性成分在药物组合物中的质量百分比为1％以下；麻醉活性成分为利多卡因、丁卡因、布比卡因、阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因或普鲁卡因。该药物组合物及贴剂能够获得12-30小时的连续镇痛效果，且该贴剂能够抵抗一定外力挤压、可以保护其覆盖的配方层不被挤走，进而保持配方层的厚度。

Description

药物组合物、贴剂及其制备方法、镇痛方法、应用
本申请要求申请日为2018年01月17日的中国专利申请CN201810045015.8的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种药物组合物、贴剂及其制备方法、镇痛方法、应用。
背景技术
局部麻醉药制剂被用于预防或治疗皮肤或粘膜的疼痛，例如：2％盐酸利多卡因凝胶用于减轻与晒伤有关的疼痛；恩纳(英文名称EMLA)是一种含利多卡因和丙胺卡因低点共融油滴的乳剂，其用于伴有疼痛的手术前完整皮肤的麻醉；Lidoderm是一种含5％利多卡因的固化凝胶贴剂，其用于减轻带状疱疹后遗神经痛(皮肤本身是完整的)；Pliaglis是一种含7％利多卡因和7％丁卡因低点共融油滴形的乳剂，其用于伴有疼痛的手术前完整皮肤的麻醉。但是，上述各局部麻醉药均各有严重的局限性。例如：盐酸利多卡因凝胶不能麻醉完整皮肤；EMLA中的丙胺卡因会引起高铁血红蛋白血症；Pliaglis中的丁卡因会引起与酯类局麻药有关的过敏反应，且丁卡因会被水解，故Pliaglis必须冷藏储存，以降低水解速度；Lidoderm无法在120分钟内，甚至4小时内麻醉完整的皮肤，且Lidoderm每次使用时间不能超过12小时。然而，上述各局部麻醉药制剂共同的局限在于不能实现长时间连续安全镇痛效果。
在许多疾病的治疗中，理想的产品是能够有12、18、24、甚至30小时的连续镇痛效果。因此，寻求一种具有长期连续安全镇痛效果的药物组合物是目前亟须解决的问题。
此外，为了实现药物组合物对患处的长期镇痛效果，覆盖在患处的配方层的厚度是很重要的。如果配方层太薄，配方层里的局部麻醉药会被过早地吸收完，以至于得不到预期的镇痛时间。而现有技术中，通常将配方层涂抹于患处后，再用医用薄膜覆盖，在镇痛期间，配方层受到外力挤压后，会导致患处的配方层变薄，进而大大缩短有效镇痛时间。因此，寻求一种能够保证配方层厚度的贴剂也是目前亟须解决的问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中的局部麻醉药制剂共同的局限性在于不能实现长时间连续安全镇痛效果的缺陷，而提供一种药物组合物、贴剂及其制备 方法、镇痛方法、应用。该药物组合物及贴剂能够获得12、18、24、甚至30小时的连续安全镇痛效果，且该贴剂能够抵抗一定外力挤压、可以保护其覆盖的配方层不被挤走，进而保持配方层的厚度。
本发明通过以下技术方案解决上述技术问题：
本发明提供一种药物组合物，所述药物组合物包括单一的麻醉活性成分，所述麻醉活性成分包括溶解于水的麻醉活性成分和以未溶解状态存在的麻醉活性成分；所述麻醉活性成分在所述药物组合物中的质量百分比为2％以上；所述溶解于水的麻醉活性成分在所述药物组合物中的质量百分比为1％以下；所述麻醉活性成分为利多卡因、丁卡因、布比卡因、阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因或普鲁卡因。
本发明的药物组合物能够获得12、18、24、甚至30小时的连续镇痛效果(例如：为手术后切口伤疼痛的病人在切口伤处提供24小时以上的镇痛效果；为带状疱疹后神经痛的病人在痛处皮肤上提供12小时或24小时以上镇痛效果)。该制剂(发明内容中，所述的“制剂”指的即为本发明的药物组合物)可用于带状疱疹疱疹期疼痛、带状疱疹后神经损害疼痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节疼痛、骨性关节炎疼痛、背部疼痛、痛风所引起的疼痛、软组织损伤所引起的疼痛、手术后切口疼痛、烧伤疼痛或烧伤去痂时的疼痛的镇痛。
与本发明中和市场上的药物组合物(含有两个或以上局部麻醉药成分的产品，如恩纳)相比，利多卡因作为单一的麻醉活性成分的制剂具有更好的优势：(1)该制剂更安全、易批准、可长期使用(可连续使用三个月以上)，具体来说：①利多卡因是使用最普遍的局部麻醉药，其安全性好是普遍知道的；②该制剂更容易被政府有关部门(如中国和美国的药监局)批准市场使用；③利多卡因是美国药监局唯一批准的可以长期使用(典型的定义是三个月以上)的局部麻醉药(对于许多需要长期镇痛的疾病来说，能够批准长期使用非常重要，例如：在带状疱疹后神经痛的镇痛应用中，病人可能会需要使用镇痛制剂许多年，如果一个制剂里含有的局部麻醉药不是利多卡因，这个制剂必须经过一些非常费时和费钱的试验，如长期毒理试验，才能得到批准用于长期使用)；(2)该制剂能在120分钟内、甚至90分钟内，麻醉完整皮肤，具体来说：在90分钟内或120分钟内麻醉完整皮肤的能力也是非常重要的，因为及时解除病人的痛苦，尤其是带状疱疹后神经痛那样的疼痛，对病人是很重要的；(3)该制剂也可用于非完整皮肤的镇痛(例如手术后切口伤和带状疱疹疱疹期疼痛的镇痛)。
本发明中，所述麻醉活性成分在所述药物组合物中的质量百分比还可为3％以上、4％ 以上、5％以上、8％以上或10％以上，例如可为3％-15％、4％-10％或5％-8％。
本发明中，所述溶解于水的麻醉活性成分在所述药物组合物中的质量百分比还可为0.7％以下、0.5％-0.7％或0.5％以下。
本发明中，所述麻醉活性成分的颗粒可为本领域常规使用的麻醉活性成分的颗粒，较佳地，80％以上的所述麻醉活性成分的颗粒的单颗重量为0.01-10毫克。
本发明中，所述药物组合物较佳地包括增稠剂，加入增稠剂可以增加制剂的粘滞度和防止涂在皮肤上的制剂从靶区皮肤流开。所述增稠剂较佳地为淀粉、卡波姆和纤维素中的一种或多种，更佳地为淀粉、羟乙基纤维素和羟丙基纤维素中的一种或多种。所述增稠剂在所述药物组合物中的质量百分比较佳地为0.02％-4％，更佳地为0.02％-2％，进一步更佳地为0.02％-1％。
本发明中，所述药物组合物较佳地包括甘油和/或丙二醇，加入甘油和/或丙二醇可以降低刺激皮肤的风险。所述甘油和/或丙二醇在所述药物组合物中的质量百分比较佳地为2％-25％。
本发明中，所述药物组合物较佳地包括悬浮剂，所述悬浮剂可为本领域常规使用的悬浮剂，所述悬浮剂较佳地为卡波姆，所述悬浮剂的型号较佳地为Pemulen TR-2，生产厂家为美国Lubrizol公司。所述悬浮剂在所述药物组合物中的质量百分比较佳地为0.10％-0.50％。
本发明中，所述药物组合物的pH值可为7以上或8以上，例如可为7-13、7-11或7.5-9.5。可采用本领域常规使用的pH值调节剂将所述药物组合物的pH值调节至上述pH范围，例如：可采用三聚磷酸钠、碳酸氢钠、氢氧化钠和氢氧化钾中的一种或多种；较佳地采用氢氧化钠和/或氢氧化钾。更佳地，采用氢氧化钠。进一步更佳地，当所述药物组合物中采用Pemulen TR-2为悬浮剂时，所述氢氧化钠与所述Pemulen TR-2的质量比为9:16以上。
本发明中，当所述麻醉活性成分为丁卡因时，较佳地，所述丁卡因在所述药物组合物中的质量百分比为0.5％以上，所述溶解于水的丁卡因在所述药物组合物中的质量百分比为0.1％以下。
本发明还提供一种前述的药物组合物的制备方法，所述制备方法包括如下步骤：将所述药物组合物中的各个组分混合即可。
较佳地，所述制备方法包括下述步骤：(1)将所述药物组合物中的除所述麻醉活性成分之外的其余组分混合，得混合液；(2)将所述混合液与所述麻醉活性成分进行加热，再冷却至室温即可。
步骤(2)中，所述加热的温度较佳地为75-85℃，例如可为80℃。
步骤(2)中，所述加热较佳地在搅拌下进行。
本发明还提供一种贴剂，所述贴剂包括覆盖膜和前述的药物组合物，所述覆盖膜与皮肤的接触面设有至少一个凹陷，所述凹陷的开口的面积占所述接触面的总面积的70％以上，但不包括100％，所述凹陷填有所述药物组合物。
本发明中，所述覆盖膜可由多种材料或材料的组合来制造，一般为柔软但又不容易被压瘪的材料，可选地为泡沫塑料，如聚氨酯。
上述技术方案中，该覆盖膜有一定的结构和硬度，该覆盖膜还设有凹陷结构，在该覆盖膜外侧受到压力时，在凹陷结构中的配方不容易被挤得离开患处。
本发明中，所述覆盖膜的水蒸汽通透率较佳地为100-10000g/m 2/24小时，更佳地为400-4000g/m 2/24小时。所述水蒸汽通透率(英文全称为moisture vapor transmission rate，英文缩写为MVTR)根据业内通用方法测量。上述限定范围内的材质及蒸汽通透率可更好地实现患处的皮肤的正常呼吸。
本发明中，所述覆盖膜的厚度较佳地为1-20毫米，更佳地为3-10毫米。
本发明中，所述覆盖膜的长度较佳地为3-50厘米，更佳地为8-30厘米。
本发明中，所述覆盖膜的面积较佳地为5-1000平方厘米，更佳地为10-500平方厘米。
本发明中，所述凹陷的构造较佳地为长方体、圆柱体和半球体中的一种或多种。更佳地，所述圆柱体的轴线与所述接触面垂直，所述半球体的轴线与所述接触面垂直。进一步更佳地，所述凹陷的构造为半球体，且每一所述凹陷的开口均与其相邻的所述凹陷的开口相切。
本发明中，所述凹陷的深度可为10mm以下，较佳地为0.2-10毫米，更佳地为0.5-3毫米。
本发明中，所述覆盖膜可仅设有一个凹陷，所述凹陷具有一个凹陷腔，所述凹陷的开口宽度较佳地为2-40毫米，更佳地为3-20毫米；所述凹陷的开口长度较佳地为2-50厘米，更佳地为5-20厘米。
本发明中，所述覆盖膜还可设有两个以上的凹陷，所述覆盖膜的每平方厘米上所述凹陷的数量较佳地为0.2-100个，更佳地为0.5-20个；相邻两个所述凹陷的间距较佳地为0-5毫米，更佳地为0-2毫米。进一步更佳地，相邻两个所述凹陷之间不连通。
本发明中，所述覆盖膜仅设有一个凹陷，所述凹陷具有一个凹陷腔，所述凹陷腔与皮肤的接触面设有若干第一通孔，所述凹陷腔内包括一层或一层以上的储药腔单元，每 层所述储药腔单元包括若干微储药腔，每个所述微储药腔的侧壁设有第二通孔，所述第二通孔用于连通相邻两个所述微储药腔；所述第一通孔的开口面积占所述第一表面的总面积的70％以上、但不包括100％。
其中，较佳地，所有所述微储药腔共同形成丝瓜瓤状的网络结构。
其中，较佳地，所述微储药腔是形状为正六棱柱的空腔，所述微储药腔以蜂窝结构排布。
其中，较佳地，相邻两层的所述微储药腔还交错设置。
其中，较佳地，所述凹陷腔除所述第一表面外的其余表面为封闭结构。
本发明中，所述凹陷的深度较佳地与所述覆盖膜的厚度相等。
其中，所述凹陷远离所述开口的一侧可部分附有屏障膜。
其中，所述凹陷远离所述开口的一侧可全部附有屏障膜。当凹陷远离开口的一侧全部附有屏障膜时，形成的覆盖膜为覆盖组合。
上述技术方案中，凹陷的深度与覆盖膜的厚度相等，则是为了便于加工制造。而有些配方在使用过程中，须保持已经施用在皮肤、伤口或粘膜上的配方层里的水分。保持水分的方法之一是将凹陷远离开口的一侧附上一层屏障膜，如塑料薄膜或聚氨酯膜，从而形成覆盖组合，再将该覆盖组合覆盖住配方层即可。如果配方层施用在一个会渗出体液的伤口上，那么，凹陷远离开口的一侧可不附有屏障膜或部分附有屏障膜。
本发明中，较佳地，所述凹陷的构造相同，且所述凹陷均匀排布或以阵列方式排布。
本发明中，所述覆盖膜中的凹陷处填有所述药物组合物，所述开口与患处直接接触，此时，所述开口的面积为药物组合物与患处直接接触的面积。
本发明中，所述开口的外缘可为一条连续的封闭曲线，可为若干相切的封闭曲线，可为若干仅有一个交点的封闭曲线，也可为若干没有交点的封闭曲线。
本发明中，所述间距指的是相邻两个所述开口的外缘之间的最小距离。
本发明还提供一种前述的药物组合物在制备治疗带状疱疹疱疹期疼痛、带状疱疹后神经损害疼痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节疼痛、骨性关节炎疼痛、背部疼痛、痛风所引起的疼痛、软组织损伤所引起的疼痛、手术后切口疼痛、烧伤疼痛或烧伤去痂时的疼痛的药物中的应用。
本发明还提供一种前述的贴剂在制备治疗带状疱疹疱疹期疼痛、带状疱疹后神经损害疼痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节疼痛、骨性关节炎疼痛、背部疼痛、痛风所引起的疼痛、软组织损伤所引起的疼痛、手术后切口疼痛、烧伤疼痛或烧伤去痂时的疼痛的医疗器械中的应用。
本发明还提供一种采用前述的药物组合物的镇痛方法，所述镇痛方法包括如下步骤：将所述药物组合物涂抹在患处皮肤上，再用屏障膜覆盖所述药物组合物即可。
本发明中，所述患处皮肤例如可为带状疱疹疱疹期疼痛处皮肤、带状疱疹后神经损害疼痛处皮肤、神经瘤疼痛处皮肤、幻肢痛处皮肤、糖尿病周围神经痛处皮肤、关节疼痛处皮肤、骨性关节炎疼痛处皮肤、背部疼痛处皮肤、痛风所引起的疼痛处皮肤、软组织损伤所引起的疼痛处皮肤、手术后切口疼痛处皮肤、烧伤疼痛处皮肤或烧伤去痂时疼痛处皮肤。
本发明中，保持所述药物组合物在所述患处皮肤的时间较佳地为8小时以上、12小时以上、18小时以上、24小时以上或30小时以上。
本发明中，保持所述药物组合物在所述患处皮肤的厚度较佳地不低于0.5毫米、不低于1毫米或不低于2毫米。
本发明还提供一种采用前述的贴剂的镇痛方法，所述镇痛方法包括如下步骤：将所述贴剂中所述凹陷的开口与患处皮肤接触即可。
本发明中，所述患处皮肤例如可为带状疱疹疱疹期疼痛处皮肤、带状疱疹后神经损害疼痛处皮肤、神经瘤疼痛处皮肤、幻肢痛处皮肤、糖尿病周围神经痛处皮肤、关节疼痛处皮肤、骨性关节炎疼痛处皮肤、背部疼痛处皮肤、痛风所引起的疼痛处皮肤、软组织损伤所引起的疼痛处皮肤、手术后切口疼痛处皮肤、烧伤疼痛处皮肤或烧伤去痂时疼痛处皮肤。
本发明中，保持所述贴剂在所述患处皮肤的时间较佳地为8小时以上、12小时以上、18小时以上、24小时以上或30小时以上。
本发明中，保持所述贴剂中的所述药物组合物在所述患处皮肤的厚度较佳地不低于0.5毫米、不低于1毫米或不低于2毫米。
本发明中，完整皮肤或完整正常人类皮肤，是指对异物的主要屏障(角质层)为完整的皮肤。
本发明中，所述百分比是指质量百分比，除非有特别说明。
本发明中，“能够在120分钟内麻醉完整正常人类皮肤”之类的词句是指在正常室温下施用所述药物组合物后大多数人的皮肤会在所述的时间内被麻醉，从医学角度理解，本领域技术人员均知晓这类话的描述不一定是每一个人的皮肤会在所述的时间内被麻醉。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明提供一种药物组合物、贴剂及其制备方法、镇痛方法、应用。该制剂及贴剂能够获得12、18、24、甚至30小时的连续安全镇痛效果，且该贴剂能够抵抗一定外力挤压、可以保护其覆盖的配方层不被挤走，进而保持配方层的厚度。该制剂可用于带状疱疹疱疹期疼痛、带状疱疹后神经损害疼痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节疼痛、骨性关节炎疼痛、背部疼痛、痛风所引起的疼痛、软组织损伤所引起的疼痛、手术后切口疼痛、烧伤疼痛或烧伤去痂时的疼痛的镇痛。
与本发明中和市场上的其他药物组合物(含有两种或更多种局部麻醉药有效成分的产品，如恩纳)相比，利多卡因作为单一的麻醉活性成分的制剂具有更好的优势：(1)该制剂更安全、易批准、可长期使用(连续使用三个月以上)；(2)该制剂能在120分钟内、甚至90分钟内，麻醉完整皮肤；(3)该制剂也可用于非完整皮肤的镇痛。
附图说明
图1为实施例27的贴剂的覆盖膜及屏障膜的结构示意图。
图2为实施例27的贴剂的覆盖组合的结构示意图。
图3为实施例28、32-36的贴剂的覆盖膜及屏障膜的结构示意图。
图4为实施例28、32-36的贴剂的覆盖组合的结构示意图。
图5为实施例29-31的贴剂的覆盖膜及屏障膜的结构示意图。
图6为实施例29-31的贴剂的覆盖组合的结构示意图。
图7为实施例37-41的贴剂的覆盖膜及屏障膜的结构示意图。
图8为实施例37-41的贴剂的覆盖组合的结构示意图。
图9为实施例42的贴剂的覆盖膜及屏障膜的结构示意图。
图10为实施例42的贴剂的覆盖组合的结构示意图。
图11为实施例43-46的贴剂的覆盖膜的结构示意图。
图12为实施例43-46的贴剂的覆盖组合的结构示意图。
附图标记说明：
凹陷1
屏障膜2
粘贴层3
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施 例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1-24中，麻醉活性成分的颗粒中，80％以上的麻醉活性成分的颗粒的单颗重量为0.01-10毫克。
实施例1
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 4
Pemulen TR-2 0.24
氢氧化钠 0.13
水 补足至100
所述药物组合物的制备方法如下：
将氢氧化钠和悬浮剂卡波姆Pemulen TR-2加入水中，搅拌直至获得均匀粘滞的液体。然后，加入利多卡因晶体，并加热到80℃，快速搅拌后，冷却至室温，即得。
效果数据：将所得药物组合物记为配方A，所得药物组合物为含有溶解的利多卡因和未溶解的利多卡因的粘滞溶液，其中未溶解的利多卡因以悬浮晶体的形式存在于粘滞溶液中；所得药物组合物的pH值高于8；每毫升溶液中利多卡因共40毫克，其中：约5毫克是溶解的利多卡因，约35毫克是未溶解的悬浮的利多卡因晶体。
实施例2
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 5
Pemulen TR-2 0.24
氢氧化钠 0.13
淀粉 0.3
水 补足至100
所述药物组合物的制备方法如下：
将氢氧化钠和悬浮剂卡波姆Pemulen TR-2加入水中，搅拌直至获得均匀粘滞的液体。然后，加入利多卡因晶体和淀粉，并加热到80℃，快速搅拌后，冷却至室温，即得。
效果数据：将所得药物组合物记为配方B，所得药物组合物为含有溶解的利多卡因和未溶解的利多卡因的粘滞溶液，其中未溶解的利多卡因以悬浮晶体的形式存在于粘滞溶液中；所得药物组合物的pH值高于8；每毫升溶液中利多卡因共50毫克，其中：约5毫克是溶解的利多卡因，约45毫克是未溶解的悬浮的利多卡因晶体。
实施例3
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 5
Pemulen TR-2 0.25
氢氧化钠 0.14
淀粉 0.3
甘油 15
水 补足至100
所述药物组合物的制备方法如下：
将氢氧化钠和悬浮剂卡波姆Pemulen TR-2加入水中，搅拌直至获得均匀粘滞的液体。然后，加入利多卡因晶体、淀粉和甘油，并加热到80℃，快速搅拌后，冷却至室温，即得。
效果数据：将所得药物组合物记为配方C，所得药物组合物为含有溶解的利多卡因和未溶解的利多卡因的粘滞溶液，其中未溶解的利多卡因以悬浮晶体的形式存在于粘滞溶液中；所得药物组合物的pH值高于8；大部分利多卡因以未溶解的悬浮的晶体的形式存在。
实施例4
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 10
Pemulen TR-2 0.24
氢氧化钠 0.13
淀粉 0.3
水 补足至100
所述药物组合物的制备方法同实施例2。
效果数据：将所得药物组合物记为配方D，所得药物组合物为含有溶解的利多卡因和未溶解的利多卡因的粘滞溶液，其中未溶解的利多卡因以悬浮晶体的形式存在于粘滞溶液中；所得药物组合物的pH值高于8；每毫升溶液中利多卡因共100毫克，其中：约5毫克是溶解的利多卡因，约95毫克是未溶解的悬浮的利多卡因晶体。
实施例5
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 15
Pemulen TR-2 0.24
氢氧化钠 0.13
淀粉 0.3
水 补足至100
所述药物组合物的制备方法同实施例2。
效果数据：将所得药物组合物记为配方E，所得药物组合物为含有溶解的利多卡因和未溶解的利多卡因的粘滞溶液，其中未溶解的利多卡因以悬浮晶体的形式存在于粘滞溶液中；所得药物组合物的pH值高于8；每毫升溶液中利多卡因共150毫克，其中：约5毫克是溶解的利多卡因，约145毫克是未溶解的悬浮的利多卡因晶体。
实施例6
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
布比卡因 4
Pemulen TR-2 0.25
氢氧化钠 0.16
淀粉 0.4
水 补足至100
所述药物组合物的制备方法如下：
将氢氧化钠和悬浮剂卡波姆Pemulen TR-2加入水中，搅拌直至获得均匀粘滞的液体。然后，加入布比卡因晶体和淀粉，并加热到80℃，快速搅拌后，冷却至室温，即得。
效果数据：将所得药物组合物记为配方F，所得药物组合物的布比卡因总量中，只有不到四分之一是溶解的，其余都以颗粒的形式存在，也即溶解的布比卡因的质量分数低于1％，所述百分比为所述溶解的布比卡因的质量占所得药物组合物的总质量的百分比。
实施例7
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
丁卡因 4
Pemulen TR-2 0.25
氢氧化钠 0.16
淀粉 0.4
水 补足至100
所述药物组合物的制备方法如下：
将氢氧化钠和悬浮剂卡波姆Pemulen TR-2加入水中，搅拌直至获得均匀粘滞的液体。然后，加入丁卡因晶体和淀粉，并加热到80℃，快速搅拌后，冷却至室温，即得。
效果数据：将所得药物组合物记为配方G，所得药物组合物的丁卡因总量中，只有不到十分之一是溶解的，其余都以颗粒的形式存在，也即溶解的丁卡因的质量分数低于0.4％，所述百分比为所述溶解的丁卡因的质量占所得药物组合物的总质量的百分比。
实施例8-18
将实施例1中的麻醉活性成分分别用阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因、普鲁卡因替换，即得实施例8-18。
效果数据：所得药物组合物为含有溶解的麻醉活性成分和未溶解的麻醉活性成分的粘滞溶液，其中未溶解的麻醉活性成分以悬浮晶体的形式存在于粘滞溶液中；所得药物组合物的pH值高于8；每毫升溶液中麻醉活性成分共40毫克，其中：约5毫克是溶解的，约35毫克是未溶解的悬浮晶体。
实施例19
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 2
氢氧化钠 0.13
水 补足至100
所述药物组合物的制备方法如下：
将氢氧化钠加入水中，搅拌均匀，然后，加入利多卡因晶体，并加热到80℃，快速搅拌后，冷却至室温，即得。
效果数据：所得药物组合物的pH值高于8；每毫升溶液中利多卡因共20毫克，其中：约5毫克是溶解的利多卡因，约15毫克是未溶解的悬浮的利多卡因晶体。
实施例20
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 3
Pemulen TR-2 0.24
氢氧化钠 0.13
水 补足至100
制备方法同实施例1。所得药物组合物的pH值高于8；每毫升溶液中利多卡因共30毫克，其中：约5毫克是溶解的利多卡因，约25毫克是未溶解的悬浮的利多卡因晶体。
实施例21
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 8
Pemulen TR-2 0.24
氢氧化钠 0.13
淀粉 0.02
甘油 2
水 补足至100
制备方法同实施例3。所得药物组合物的pH值高于8；每毫升溶液中利多卡因共80毫克，其中：约5毫克是溶解的利多卡因，约75毫克是未溶解的悬浮的利多卡因晶体。
实施例22
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 15
Pemulen TR-2 0.24
氢氧化钠 0.13
淀粉 4
甘油 25
水 补足至100
制备方法同实施例3。所得药物组合物的pH值高于8；每毫升溶液中利多卡因共150毫克，其中：约5毫克是溶解的利多卡因，约145毫克是未溶解的悬浮的利多卡因晶体。
实施例23
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 10
Pemulen TR-2 0.24
氢氧化钠 0.14
淀粉 1
水 补足至100
制备方法同实施例2。所得药物组合物的pH值高于8；每毫升溶液中利多卡因共100毫克，其中：约7毫克是溶解的利多卡因，约93毫克是未溶解的悬浮的利多卡因晶体。
实施例24
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
丁卡因 0.5
Pemulen TR-2 0.24
氢氧化钠 0.14
水 补足至100
制备方法同实施例1，不同之处在于麻醉活性成分为丁卡因。所得药物组合物的pH值高于8；每毫升溶液中丁卡因共5毫克，其中：约1毫克是溶解的丁卡因，约4毫克是未溶解的悬浮的丁卡因晶体。
实施例25
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 10
Pemulen TR-2 0.1
氢氧化钠 0.06
水 补足至100
制备方法同实施例1。所得药物组合物的pH值高于8；每毫升溶液中利多卡因共100毫克，其中：约7毫克是溶解的利多卡因，约93毫克是未溶解的悬浮的利多卡因晶体。
实施例26
一种药物组合物的原料组合物，其成分如下表所示：
成分 质量百分比/％
利多卡因 10
Pemulen TR-2 0.5
氢氧化钠 0.29
水 补足至100
制备方法同实施例1。所得药物组合物的pH值高于8；每毫升溶液中利多卡因共100毫克，其中：约7毫克是溶解的利多卡因，约93毫克是未溶解的悬浮的利多卡因晶体。
实施例27
一种贴剂，其包括如图1所示的覆盖膜和配方D，该覆盖膜为聚氨酯膜，该覆盖膜的水蒸汽通透率为100g/m 2/24小时，厚度为3毫米，长度为10厘米，面积为15平方厘米。该覆盖膜与皮肤的接触面设有若干凹陷1，该凹陷1的构造为长方体，且以阵列方式排布，该覆盖膜的每平方厘米上凹陷的数量为0.8个，每一凹陷的深度均为3毫米，相邻两个凹陷的间距为2毫米，凹陷的开口面积占接触面总面积的70％。凹陷远离开口的一侧还附有屏障膜2，从而形成图2所示的覆盖组合，该屏障膜2为聚氨酯膜，该屏障膜2的水蒸汽通透率为100g/m 2/24小时。所述配方充满所述凹陷。
实施例28-31
实施例28-31的贴剂所使用的覆盖膜组合的结构参数如下，其余同实施例27；所述配方D充满所述凹陷。
其中，实施例28的覆盖膜及屏障膜的结构示意图如图3所示，其形成的覆盖组合如图4所示。其中，实施例29-31的覆盖膜及屏障膜的结构示意图如图5所示，其形成的覆盖组合如图6所示。
Figure PCTCN2019071898-appb-000001
Figure PCTCN2019071898-appb-000002
实施例32
一种贴剂，其包括如图3所示的覆盖膜和配方D，该覆盖膜为聚氨酯膜，该覆盖膜的水蒸汽通透率为100g/m 2/24小时。该覆盖膜与皮肤的接触面设有一个凹陷1，该凹陷1的构造为长方体，凹陷1的深度为3毫米，凹陷1的开口宽度为15毫米，凹陷1的开口长度为5厘米，凹陷1的开口面积占接触面总面积的70％。凹陷1远离开口的一侧还附有屏障膜2，从而形成图4所示的覆盖组合，该屏障膜2为聚氨酯膜，该屏障膜2的水蒸汽通透率为100g/m 2/24小时。所述配方D充满所述凹陷。
实施例33-36
实施例33-36的贴剂所使用的覆盖膜组合的结构参数如下，其余同实施例32；所述配方D充满所述凹陷。
Figure PCTCN2019071898-appb-000003
实施例37
一种贴剂，其包括如图7所示的覆盖膜和配方D，该覆盖膜为聚氨酯膜，该覆盖膜的水蒸汽通透率为100g/m 2/24小时，厚度为3毫米，长度为10厘米，面积为15平方厘米。该覆盖膜与皮肤的接触面设有若干凹陷1，该凹陷1的构造为半球体，半球体的高与接触面垂直，且该凹陷均匀分布，该覆盖膜的每平方厘米上凹陷的数量为0.8个，每个半球体凹陷的高度均为3毫米，凹陷1的开口面积占接触面总面积的70％，相邻两个半球体的底面外缘相切。凹陷1远离开口的一侧还附有屏障膜2，从而形成图8所示的覆盖组合，该屏障膜2为聚氨酯膜，该屏障膜2的水蒸汽通透率为100g/m 2/24小时。所述配方D充满所述凹陷。
实施例38-41
实施例38-41的贴剂所使用的覆盖膜组合的结构参数如下，其余同实施例37；所述配方D充满所述凹陷。
Figure PCTCN2019071898-appb-000004
实施例42
一种贴剂，其包括如图9所示的覆盖膜和配方D，该覆盖膜为聚氨酯膜，该覆盖膜的水蒸汽通透率为100g/m 2/24小时，厚度为3毫米，长度为10厘米，面积为15平方厘米。该覆盖膜仅设有一个凹陷1，该凹陷具有一个凹陷腔和环绕该凹陷腔的粘贴层3，该凹陷腔的深度为3毫米，该凹陷腔具有与皮肤接触的第一表面，该第一表面设有若干第一通孔，该第一通孔的开口面积占该第一表面的总面积的70％。该凹陷腔内包括一层以上的储药腔单元，每层所述储药腔单元包括若干微储药腔，每个所述微储药腔的侧壁设有第二通孔(图中未标出)，该第二通孔用于连通相邻两个所述微储药腔。所有微储药腔共同形成丝瓜瓤状的网络结构。该覆盖膜远离第一通孔的一侧还附有屏障膜2，从而形成图10所示的覆盖组合，该屏障膜2为聚氨酯膜，该屏障膜2的水蒸汽通透率为100g/m 2/24小时。所述配方D充满所述凹陷。
实施例43
如图11所示的覆盖膜，该覆盖膜为聚氨酯膜，该覆盖膜的水蒸汽通透率为400g/m 2/24小时，厚度为0.2毫米，长度为3厘米，面积为5平方厘米。该覆盖膜仅设有一个凹陷1，该凹陷具有一个凹陷腔和环绕该凹陷腔的粘贴层3，该凹陷腔的深度为0.2毫米，该凹陷腔具有与皮肤接触的第一表面，该第一表面设有若干第一通孔，该第一通孔的开口面积占该第一表面的总面积的70％。该凹陷腔内包括一层以上的储药腔单元，每层所述储药腔单元包括若干微储药腔，每个所述微储药腔的侧壁设有第二通孔(图中未标出)，该第二通孔用于连通相邻两个所述微储药腔。该微储药腔是形状为正六棱柱的空腔，且以蜂窝结构排布，相邻两层的所述微储药腔还交错设置。该覆盖膜远离第一通孔的一侧还附有屏障膜2，从而形成图12所示的覆盖组合，该屏障膜2为聚氨酯膜，该屏障膜2 的水蒸汽通透率为400g/m 2/24小时。所述配方D充满所述凹陷。
实施例44-46
实施例44-46的贴剂所使用的覆盖膜组合的结构参数如下，其余同实施例43；所述配方D充满所述凹陷。
Figure PCTCN2019071898-appb-000005
效果实施例1
将一层2毫米厚的配方A涂抹在一块无纺布上，一部分配方A被吸收到了无纺布里面。这块吸收了配方A的无纺布被放在了一个人类受试者的上臂的皮肤上，并用一层不透的塑料薄膜盖住。该塑料薄膜被胶膜固定在皮肤上。被配方A覆盖的皮肤在约90分钟后被麻醉。在开始用药24小时后，配方A被从皮肤上取下。被配方A覆盖的皮肤在配方A被取下时和取下一小时后都还是处于被麻醉的状态。
效果实施例2
一个病人的背部皮肤已经患带状疱疹后遗神经痛6年以上。将约1毫米厚的一层配方B涂抹在患处皮肤上，并用一层不透气的塑料薄膜覆盖住配方层。用胶膜将塑料薄膜固定在皮肤上。塑料薄膜是为了防止配方中的水分蒸发。约90分钟以后，该病人的疼痛感开始明显减轻。该病人将此配方和塑料薄膜在皮肤上维持了18小时，然后将它们取下。该病人有将近20小时的基本无痛时间：从开始用药90分钟后在终止用药后的数小时。这个非常满意的镇痛效果比她在过去6年中曾经用过的任何药都好，并让她睡了一个好觉。在接下来的数月中，她反复用同样方法使用了配方B和实施例的其他配方，包括配方C，并且都取得了类似的满意效果。
效果实施例3
一个病人的小腿部18×18厘米的皮肤和两个脚趾的皮肤患带状疱疹，在疱疹期。患处皮肤非常疼痛和红肿。将约1毫米厚的配方C覆盖在患处皮肤上并用一层塑料薄膜盖住配方，以防止配方里的水分蒸发。配方和塑料薄膜在皮肤上保持了25小时。除了第一小时，病人在这25小时内几乎没有感觉到痛。在配方被取下后，患处皮肤的红肿也大大减轻。4小时以后，该病人又用类似方法使用了配方C。而这次配方C覆盖皮肤的厚度是 约2毫米。病人在35小时后将配方和塑料薄膜取下。除了第一个小时，在这35小时中，该病人都得到了非常满意的镇痛效果。
效果实施例4
一个病人的整个右腿和部分骨盆由于骨癌的原因被切除。切除手术后，她感觉到切口面的皮肤的剧烈疼痛(切口面被病人自己的在手术时留下的皮肤覆盖)。医生们认为这个疼痛是手术导致的神经损害所引起的。另外，她还感觉到已经不存在的右小腿患有剧烈的幻肢痛(幻肢痛是一种截肢病人经常感觉到的，在已经不存在的肢体上的疼痛。)。为了减轻这两种疼痛，医护人员把约1毫米厚的配方C涂抹在患处皮肤上，并用一层边上带胶的塑料薄膜覆盖住配方。一小时以后，她的皮肤痛和幻肢痛就基本消失了。她将配方在皮肤上保持了24小时。有效的镇痛效果在配方被取下后还维持24小时左右。这位病人在以后的许多星期中每两天重复一次上述的用药。镇痛效果非常满意，以致她在大多数时间都不需要口服止痛药。配方C能有效地减轻幻肢痛是一个很意外的发现。
效果实施例5
一个病人的背部30×30厘米的皮肤和胸部15×15厘米的皮肤患严重带状疱疹后遗神经痛约8年。所有用过的治疗方法均没有效果。将约2毫米厚的配方C覆盖在患处皮肤上并用一层塑料薄膜盖住配方。一小时后，病人的疼痛开始明显减轻。配方和塑料薄膜在皮肤上保持了36小时后被取下。除了第一小时外，在这36小时内，镇痛效果都非常满意。
效果实施例6
为了减轻一位剖腹产病人的手术切口疼痛，医护人员把一层3毫米厚，1.5厘米宽的配方D覆盖在缝合后的手术切口上，并用图2所示的覆盖组合覆盖住配方D。配方中的利多卡因分子马上开始渗入切口和周围的组织。病人的手术切口疼痛在15分钟内就开始有明显的减轻。满意的镇痛效果持续了12小时以上。当病人再次感到疼痛时，医护人员取下了配方D和覆盖组合，然后用同样的操作方法再次使用了配方D和覆盖组合。以后，每当病人有镇痛需求时，医护人员都用同样的操作方法使用配方D和覆盖组合。
效果实施例7
为了减轻一位胆囊摘除病人的手术切口疼痛，医护人员把一层3毫米厚的配方F覆盖在缝合后的手术切口上，并用图4所示的覆盖组合覆盖住配方F。配方中的布比卡因分子马上开始渗入切口和周围的组织。病人的手术切口疼痛在15分钟内就开始有明显的减轻。满意的镇痛效果持续了12小时以上。以后，每当病人有镇痛需求时，医护人员都用同样的操作方法使用配方F和覆盖组合。
效果实施例8
为了减轻一位阑尾炎病人的手术切口疼痛，医护人员把一层3毫米厚的配方G覆盖在缝合后的手术切口上，并用一层医用胶膜覆盖住配方G。配方中的丁卡因分子马上开始渗入切口和周围的组织。病人的手术切口疼痛在10分钟内就开始有明显的减轻。满意的镇痛效果持续了24小时以上。以后，每当病人有镇痛需求时，医护人员都用同样的操作方法使用配方G和医用胶膜。
效果实施例9
一位病人双肩都患有肩周炎引起的疼痛。将1-2毫米厚的一层配方C涂抹在这个病人的双肩的皮肤上并用图6所示的覆盖组合盖住。一小时以后，病人双肩的疼痛基本上消失了。这样满意的镇痛效果在一个肩关节上持续了8小时，另外一个肩关节上持续了18小时以上。
效果实施例10
将配方A涂抹在一层已经覆盖在一个人的烧伤创面上的纱布上。此配方透过纱布渗透到创面，并将利多卡因传递进创面组织，创面的疼痛因此大大降低。因为配方的缓释功能，此镇痛效果持续了许多小时。此后，需要镇痛时，将配方层直接涂抹于烧伤创面上，并用图6所示的覆盖膜覆盖在配方层上，配方中水的蒸发速度降低，进而使得有效镇痛时间得以延长。
在创面去痂过程中引起的疼痛，采用图6所示的覆盖膜覆盖在已经涂抹在纱布上的配方层上，配方中水的蒸发速度降低，进而使得有效镇痛时间得以延长。
效果实施例11
一位病人的膝关节患有骨性关节炎所引起的疼痛。将一层约2毫米厚的配方C涂抹在整个膝关节的皮肤上，并用如图6所示的覆盖组合盖住。该病人将此配方保持在膝关节上18小时以后取下，并且每天重复同样的操作。这位病人的疼痛因此大大降低。
效果实施例12
一位病人的踝关节患有痛风所引起的疼痛。将一层约2毫米厚的配方C涂抹在整个踝关节的皮肤上，并用图6所示的覆盖组合覆盖。该病人将此配方保持在踝关节上18小时以后取下，并且每天重复同样的操作。这位病人的疼痛因此大大降低。
效果实施例13
一位病人患有背部疼痛。将一层约2毫米厚的配方C涂抹在疼痛处的皮肤上，并用图6所示的覆盖组合盖住。该病人将此配方保持在背部皮肤上18小时以后取下，并且每天重复同样的操作。这位病人的疼痛因此大大降低。
效果实施例14
将2毫米厚的实施例8-26所得药物组合物涂抹在一块无纺布上，一部分配方被吸收到了无纺布里面。这块吸收了配方的无纺布被放在了一个人类受试者的上臂的皮肤上，并用一层不透的塑料薄膜盖住。该塑料薄膜被胶膜固定在皮肤上。被配方覆盖的皮肤在约90分钟后被麻醉。在开始用药24小时后，配方从皮肤上取下。被配方覆盖皮肤在配方被取下时和取下一小时后都还是处于被麻醉的状态。
效果实施例15
为了减轻一位剖腹产病人的手术切口疼痛，医护人员把实施例27-46所述的贴剂覆盖在缝合后的手术切口上。配方中的利多卡因分子马上开始渗入切口和周围的组织。病人的手术切口疼痛在15分钟内就开始有明显的减轻。镇痛期间，该病人伴有翻身、侧卧等日常动作，该覆盖膜均起到了很好的抵抗外力挤压的作用保护其覆盖的配方层不被挤走，始终保持配方层的厚度，满意的镇痛效果持续了12小时以上。以后，每当病人有镇痛需求时，医护人员都用同样的操作方法使用配方D和覆盖组合，镇痛期间，该覆盖膜均起到了很好的抵抗外力挤压的作用保护其覆盖的配方层不被挤走，始终保持配方层的厚度。
效果实施例16
将实施例1-26的药物组合物用于带状疱疹的疱疹期的疼痛、带状疱疹后遗神经痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节痛包括骨性关节炎疼痛、软组织损伤、痛风、手术切口痛、烧烫伤痛或烧伤去痂时的疼痛，该药物组合物均能起到12-30小时的连续镇痛效果。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (14)

  1. 一种药物组合物，其特征在于，所述药物组合物包括单一的麻醉活性成分，所述麻醉活性成分包括溶解于水的麻醉活性成分和以未溶解状态存在的麻醉活性成分；所述麻醉活性成分在所述药物组合物中的质量百分比为2％以上；所述溶解于水的麻醉活性成分在所述药物组合物中的质量百分比为1％以下；所述麻醉活性成分为利多卡因、丁卡因、布比卡因、阿替卡因、辛可卡因、地布卡因、依替卡因、左布比卡因、甲哌卡因、丙胺卡因、罗哌卡因、三甲卡因、苯佐卡因或普鲁卡因。
  2. 如权利要求1所述的药物组合物，其特征在于，所述药物组合物的pH值为7以上，较佳地为8以上，更佳地为7-13、7-11或7.5-9.5；
    其中，较佳地，采用碱性物质将所述药物组合物的pH值调节至7以上、8以上、7-13、7-11或7.5-9.5，所述碱性物质为三聚磷酸钠、碳酸氢钠、氢氧化钠和氢氧化钾中的一种或多种；更佳地，所述碱性物质为氢氧化钠和/或氢氧化钾；进一步更佳地，所述碱性物质为氢氧化钠。
  3. 如权利要求1或2所述的药物组合物，其特征在于，所述麻醉活性成分在所述药物组合物中的质量百分比为3％以上、4％以上、5％以上、8％以上或10％以上；较佳地为3％-15％、4％-10％或5％-8％；
    和/或，所述溶解于水的麻醉活性成分在所述药物组合物中的质量百分比为0.7％以下、0.5％-0.7％或0.5％以下；
    和/或，所述麻醉活性成分的颗粒中，80％以上的所述麻醉活性成分的颗粒的单颗重量为0.01-10毫克。
  4. 如权利要求1-3中至少一项所述的药物组合物，其特征在于，所述药物组合物还包括悬浮剂；其中，所述悬浮剂较佳地为卡波姆，所述悬浮剂的型号较佳地为Pemulen TR-2；所述悬浮剂在所述药物组合物中的质量百分比较佳地为0.10％-0.50％；
    和/或，所述药物组合物还包括增稠剂；其中，所述增稠剂较佳地为淀粉、卡波姆和纤维素中的一种或多种，更佳地为淀粉、羟乙基纤维素和羟丙基纤维素中的一种或多种；所述增稠剂在所述药物组合物中的质量百分比较佳地为0.02％-4％，更佳地为0.02％-2％，进一步更佳地为0.02％-1％；
    和/或，所述药物组合物还包括甘油和/或丙二醇，所述甘油和/或丙二醇在所述药物组合物中的质量百分比较佳地为2％-25％。
  5. 如权利要求1-4中至少一项所述的药物组合物，其特征在于，当所述麻醉活性成 分为丁卡因时，所述丁卡因在所述药物组合物中的质量百分比为0.5％以上，所述溶解于水的丁卡因在所述药物组合物中的质量百分比为0.1％以下。
  6. 一种如权利要求1-5中任一项所述的药物组合物的制备方法，其特征在于，所述制备方法包括如下步骤：将所述药物组合物中的各个组分混合即可；
    较佳地，所述制备方法包括下述步骤：(1)将所述药物组合物中的除所述麻醉活性成分之外的其余组分混合，得混合液；(2)将所述混合液与所述麻醉活性成分进行加热，再冷却至室温即可；
    步骤(2)中，所述加热的温度较佳地为75-85℃；
    步骤(2)中，所述加热较佳地在搅拌下进行。
  7. 一种贴剂，其特征在于，所述贴剂包括覆盖膜和如权利要求1-5中任一项所述的药物组合物，所述覆盖膜与皮肤的接触面设有至少一个凹陷，所述凹陷的开口的面积占所述接触面的总面积的70％以上，但不包括100％，所述凹陷填有所述药物组合物。
  8. 如权利要求7所述的贴剂，其特征在于，所述覆盖膜的厚度为1-20毫米，较佳地为3-10毫米；所述覆盖膜的长度为3-50厘米，较佳地为8-30厘米；所述覆盖膜的面积为5-1000平方厘米，较佳地为10-500平方厘米；
    和/或，所述凹陷的构造为长方体、圆柱体和半球体中的一种或多种；其中，较佳地，所述圆柱体的轴线与所述接触面垂直，所述半球体的轴线与所述接触面垂直；更佳地，所述凹陷的构造为半球体，且每一所述凹陷的开口均与其相邻的所述凹陷的开口相切；
    和/或，所述凹陷的深度为10mm以下，较佳地为0.2-10毫米，更佳地为0.5-3毫米。
  9. 如权利要求7或8所述的贴剂，其特征在于，所述覆盖膜设有一个凹陷，所述凹陷具有一个凹陷腔，所述凹陷的开口宽度为2-40毫米，较佳地为3-20毫米；所述凹陷的开口长度为2-50厘米，较佳地为5-20厘米；
    或者，所述覆盖膜设有两个以上的凹陷，所述覆盖膜的每平方厘米上所述凹陷的数量为0.2-100个，较佳地为0.5-20个；相邻两个所述凹陷的间距为0-5毫米，较佳地为0-2毫米；其中，较佳地，相邻两个所述凹陷之间不连通；
    或者，所述覆盖膜仅设有一个凹陷，所述凹陷具有一个凹陷腔，所述凹陷腔与皮肤的接触面设有若干第一通孔，所述凹陷腔内包括一层或一层以上的储药腔单元，每层所述储药腔单元包括若干微储药腔，每个所述微储药腔的侧壁设有第二通孔，所述第二通孔用于连通相邻两个所述微储药腔；所述第一通孔的开口面积占所述第一表面的总面积的70％以上、但不包括100％；
    其中，较佳地，所有所述微储药腔共同形成丝瓜瓤状的网络结构；
    其中，较佳地，所述微储药腔是形状为正六棱柱的空腔，所述微储药腔以蜂窝结构排布；
    其中，较佳地，相邻两层的所述微储药腔还交错设置；
    其中，较佳地，所述凹陷腔除所述第一表面外的其余表面为封闭结构。
  10. 如权利要求7-9中至少一项所述的贴剂，其特征在于，所述凹陷的深度与所述覆盖膜的厚度相等；其中，较佳地，所述凹陷远离所述开口的一侧部分附有屏障膜或全部附有屏障膜；
    和/或，所述凹陷的构造相同，且所述凹陷均匀排布或以阵列方式排布；
    和/或，所述覆盖膜为泡沫塑料膜，较佳地为聚氨酯膜；其中，所述聚氨酯膜的水蒸汽通透率较佳地为100-10000g/m 2/24小时，更佳地为400-4000g/m 2/24小时。
  11. 一种如权利要求1-5中任一项所述的药物组合物在制备治疗带状疱疹疱疹期疼痛、带状疱疹后神经损害疼痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节疼痛、骨性关节炎疼痛、背部疼痛、痛风所引起的疼痛、软组织损伤所引起的疼痛、手术后切口疼痛、烧伤疼痛或烧伤去痂时的疼痛的药物中的应用。
  12. 一种如权利要求7-10中任一项所述的贴剂在制备治疗带状疱疹疱疹期疼痛、带状疱疹后神经损害疼痛、神经瘤疼痛、幻肢痛、糖尿病周围神经痛、关节疼痛、骨性关节炎疼痛、背部疼痛、痛风所引起的疼痛、软组织损伤所引起的疼痛、手术后切口疼痛、烧伤疼痛或烧伤去痂时的疼痛的医疗器械中的应用。
  13. 一种采用如权利要求1-5中任一项所述的药物组合物的镇痛方法，其特征在于，所述镇痛方法包括如下步骤：将所述药物组合物涂抹在患处皮肤上，再用屏障膜覆盖所述药物组合物即可；
    其中，所述患处皮肤较佳地为带状疱疹疱疹期疼痛处皮肤、带状疱疹后神经损害疼痛处皮肤、神经瘤疼痛处皮肤、幻肢痛处皮肤、糖尿病周围神经痛处皮肤、关节疼痛处皮肤、骨性关节炎疼痛处皮肤、背部疼痛处皮肤、痛风所引起的疼痛处皮肤、软组织损伤所引起的疼痛处皮肤、手术后切口疼痛处皮肤、烧伤疼痛处皮肤或烧伤去痂时疼痛处皮肤；
    其中，保持所述药物组合物在所述患处皮肤的时间较佳地为8小时以上、12小时以上、18小时以上、24小时以上或30小时以上；
    其中，保持所述药物组合物在所述患处皮肤的厚度较佳地不低于0.5毫米、不低于1毫米或不低于2毫米。
  14. 一种采用如权利要求7-10中任一项所述的贴剂的镇痛方法，其特征在于，所述镇痛方法包括如下步骤：将所述贴剂中所述凹陷的开口与患处皮肤接触即可；
    其中，所述患处皮肤较佳地为带状疱疹疱疹期疼痛处皮肤、带状疱疹后神经损害疼痛处皮肤、神经瘤疼痛处皮肤、幻肢痛处皮肤、糖尿病周围神经痛处皮肤、关节疼痛处皮肤、骨性关节炎疼痛处皮肤、背部疼痛处皮肤、痛风所引起的疼痛处皮肤、软组织损伤所引起的疼痛处皮肤、手术后切口疼痛处皮肤、烧伤疼痛处皮肤或烧伤去痂时疼痛处皮肤；
    其中，保持所述贴剂在所述患处皮肤的时间较佳地为8小时以上、12小时以上、18小时以上、24小时以上或30小时以上；
    其中，保持所述贴剂中的所述药物组合物在所述患处皮肤的厚度较佳地不低于0.5毫米、不低于1毫米或不低于2毫米。
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