CN106604723A - Modification of pharmaceutical preparations to make them more conducive to ultrasonic transdermal delivery - Google Patents

Modification of pharmaceutical preparations to make them more conducive to ultrasonic transdermal delivery Download PDF

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Publication number
CN106604723A
CN106604723A CN201580036489.0A CN201580036489A CN106604723A CN 106604723 A CN106604723 A CN 106604723A CN 201580036489 A CN201580036489 A CN 201580036489A CN 106604723 A CN106604723 A CN 106604723A
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CN
China
Prior art keywords
ultrasonic
excipient
medicine
percutaneous
component
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CN201580036489.0A
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CN106604723A8 (en
Inventor
小B·K·雷丁
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Bkr Ip Holdco LLC
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Bkr Ip Holdco LLC
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Publication of CN106604723A publication Critical patent/CN106604723A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0047—Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • 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
    • 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
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0092—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/08—Limbs
    • A61M2210/083—Arms
    • 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
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/10—Trunk

Abstract

A method for improving the ultrasonic transdermal delivery of an drug by modifying the excipient solution to which an active ingredient is intermixed in a drug formulation, whereby the choice of excipient solution is modified to one which will be more conducive to ultrasound and will propagate the drug substance at a higher delivery speed through the skin under ultrasonic excitation An example of such an excipient change includes a conversion from a standard dibasic sodium phosphate containing formulation to one using far less sodium or less preservative compositions. Reduced dibasic sodium phosphate formulation. Responsively to insonification thereof, including: reducing the amount of dibasic sodium phosphate in the formulation to provide a reduced dibasic sodium phosphate formulation; and, making a substance in accordance with the reduced dibasic sodium phosphate formulation.

Description

It is easier to the improvement of the pharmaceutical preparation of ultrasonic transdermal transfer
Priority request, Cross-Reference to Related Applications, by quote include and part continue
The priority of the following provisional application that the application is related to and requires to be submitted in U.S.Patent ＆ Trademark Office, and require its power Benefit：
" there is the transdermal transfer paster of the improvement of multiple absorption pads ", little Bruce K thunder fourths, on July 3rd, 2014 Submit to, application serial is 61/988,623；" the transdermal transfer device of improvement or paster and the transdermal transfer dress from the improvement The method for putting conveying insulin ", little Bruce K thunder fourths were submitted on July 3rd, 2014, and application serial is 61/998/ 622；" method that glycemic control is carried out in diabetes ", little Bruce K thunder fourths were submitted on July 3rd, 2014, application Serial number 61/998,624；" being suitable for carries out the ultrasound transfer of ultrasonic medicinal conveying by the portable and wearable system of patient Device ", little Bruce K thunder fourths were submitted on July 9th, 2014, and application serial is 61/998,683；" it is passive to can be not only used for Can be used for the enhanced method of decrease of the absorbing material of active percutaneous dosing transmission system ", little Bruce K thunder fourths, in On July 9th, 2014 submits to, and application serial is 61/998,788；" making it easier for the pharmaceutical preparation improvement of ultrasonic transdermal transfer ", Little Bruce K thunder fourths, submitted on July 9th, 2014, and application serial is 61/998,790；" for measurement in transdermal drug The method and apparatus of doses remaining in conveying device ", little Bruce K thunder fourths were submitted to, application serial on the 1st in August in 2014 For 61/999,589；" method and apparatus for affecting alternation ultrasound-transmissive in the case of non-cavitating ", little Bruce K thunders Fourth, submitted on 2 2nd, 2015, and application serial is 62/125,837；In the PCT application that U.S.Patent ＆ Trademark Office submits to：" tool Have the transdermal transfer paster of the improvement of multiple absorption pads ", little Bruce K thunder fourths were submitted on July 6th, 2015, applied for sequence Number be PCT/US15/39236；The transdermal transfer device of improvement or paster and the transdermal transfer device conveying pancreas from the improvement The method of island element, little Bruce K thunder fourths were submitted on July 6th, 2015, and application serial is PCT/US15/39264；In sugar The method that glycemic control is carried out in urine disease, little Bruce K thunder fourths were submitted to, PCT/US15/39268 on July 6th, 2015； The pharmaceutical preparation improvement of ultrasonic transdermal transfer is easier to, little Bruce K thunder fourths are submitted to, PCT/US15/ in June, 2015 39272。
The application is hereby by quoting following written descriptions whole in the provisional application that U.S.Patent ＆ Trademark Office submits to, plucking Will, the subject content in drawings and claims includes herein：
" there is the transdermal transfer paster of the improvement of multiple absorption pads ", little Bruce K thunder fourths, on July 3rd, 2014 Submit to, application serial is 61/988,623；" the transdermal transfer device of improvement or paster and the transdermal transfer dress from the improvement The method for putting conveying insulin ", little Bruce K thunder fourths were submitted on July 3rd, 2014, and application serial is 61/998, 622；" method that glycemic control is carried out in diabetes ", little Bruce K thunder fourths were submitted on July 3rd, 2014, application Serial number 61/998,624；" being suitable for carries out the ultrasound transfer of ultrasonic medicinal conveying by the portable and wearable system of patient Device ", little Bruce K thunder fourths were submitted on July 9th, 2014, and application serial is 61/998,683；" it is passive to can be not only used for Can be used for the enhanced method of decrease of the absorbing material of active percutaneous dosing transmission system ", little Bruce K thunder fourths, in On July 9th, 2014 submits to, and application serial is 61/998,788；" making it easier for the pharmaceutical preparation improvement of ultrasonic transdermal transfer ", Little Bruce K thunder fourths, submitted on July 9th, 2014, and application serial is 61/998,790；" for measurement in transdermal drug The method and apparatus of doses remaining in conveying device ", little Bruce K thunder fourths were submitted to, application serial on the 1st in August in 2014 For 61/999,589；" method and apparatus for affecting alternation ultrasound-transmissive in the case of non-cavitating ", little Bruce K thunders Fourth, submitted on 2 2nd, 2015, and application serial is 62/125,837；In the PCT application that U.S.Patent ＆ Trademark Office submits to：" tool Have the transdermal transfer paster of the improvement of multiple absorption pads ", little Bruce K thunder fourths were submitted on July 6th, 2015, applied for sequence Number be PCT/US15/39236；The transdermal transfer device of improvement or paster and the transdermal transfer device conveying pancreas from the improvement The method of island element, little Bruce K thunder fourths were submitted on July 6th, 2015, and application serial is PCT/US15/39264；In sugar The method that glycemic control is carried out in urine disease, little Bruce K thunder fourths were submitted to, PCT/US15/39268 on July 6th, 2015.
The application is the part renewal application of following co-pending fixed non-provisional application：Little Bruce K thunders fourth in The PCT/US15/39272 of entitled " being easier to the pharmaceutical preparation improvement of ultrasonic transdermal transfer " that on July 6th, 2015 submits to.
Technical field
This patent disclosure relates generally to material carrying method, and relate more specifically to suitable for enhancing skin and percutaneous thing The method of matter conveying.
Background technology
In general, transdermal drug compound or medicine, transmission system are using a kind of medicine paste for being applied to patient skin Piece.Paster allows the percutaneous skin top layer of medical compounds to absorb and in blood samples of patients.The transmission of transdermal drug compound generally may be used Mitigate the pain related to injection and intravenously administrable, while reducing the infection risk related to these technologies.Transdermal drug is defeated The intestines and stomach metabolism that it also avoid drug administration is sent, mitigates the metabolism of liver, and there is provided the sustained release of drug administration Property.Transdermal drug also enhances compliance of the patient to dosage regimen, because can relatively easily be administered and medicine is sustainable releases Put.
However, many medicines, are not well suited for being administered with conventional transdermal drug delivery systems.For example, by In molecular size or bioadhesion property, Cucumber is difficult to be absorbed by skin.In these cases, when the percutaneous medicine of trial When thing is conveyed, medicine may be gathered in the outer surface of skin, and without transdermal flux blood is entered.One example of this medicine Son is insulin, it has been found that insulin is difficult to be administered by conventional transdermal drug induction system.
All the time, conventional transdermal drug carrying method is found the medicine for being only suitable for low molecule weight, such as delaying The estradiol for solving anginal monobel, the nicotine for the scheme of giving up smoking and substituting estrogen for menopausal women.Compared with The medicine of macromolecular, such as insulin (for treating the polypeptide of diabetes), hematopoietin are (serious lean for treating Blood) and gamma interferon (for strengthening the ability of immune system fight cancer), when being with conventional transdermal drug carrying method Generally invalid compound.
A kind of method of auxiliary transdermal drug conveying is by iontherapy.Iontherapy is included in outside applying electricity , and in the non-ion entrained by the medicine of local conveying ionized form or the water flux of ion transport (electro-osmosis) correlation Chemical drug thing.To have pointed out be used for iontherapy and improve permeability of the skin to medicine.Although strengthening oozing by iontherapy It is probably thoroughly effective, but the control of drug delivery and irreversible skin damage are relevant issues caused by the technology institute.
Ultrasound is also proposed for strengthening the permeability of skin.Ultrasonic signal can be by vibration piezo-electric crystal or other motors Tool element and produce, for example by make alternating current by and produce.Permeability of the skin to drug molecule is increased using ultrasound, This sometimes referred to as ultrasound infiltration (sonophoresis) or sound permeates (phonophoresis).Although however, defeated for medicine The conventional Ultrasound application sent typically proposed, but result be it is greatly disappointed-because the enhancing to percutaneous permeability is relative Relatively low.This enters skin mainly due to being opened skin chamber and being ordered about medicine using sine wave.It is also believed that for increase is worn For crossing the drug flux of skin, effect of ultrasound is not known together.Although the success of ultrasonic infiltration of some research reports, It is that other people then obtain the result of negative.
Have found using the ultrasonic wave coupled with alternation type transonic, it is changed alternately and subsequently between a waveform To another waveform, this is avoided and conventional sinusoidal ultrasonic related hole and heat energy, and it is defeated to become a kind of effective medicine Send mechanism.Entitled material delivery apparatus, the little Bruce K thunders fourth of inventor is inventor, in October, 2008 The United States Patent (USP) 7 for authorizing for 21st, 440,798, it discloses a kind of application of the alternation type ultrasonic system for drug delivery.
In sum, exploitation is needed safely to strengthen the drug delivery through skin.
Summary of the invention
A kind of method of the ultrasonic transdermal transfer for improving medicine by improveing excipient solution, wherein in pharmaceutical preparation Active component is mixed into into the excipient solution, wherein, the selection of excipient solution be improved to be easier to ultrasound and Skin will be passed through with faster transporting velocity conveying drug substance under ultrasonic excitation.
Brief Description Of Drawings
It is considered in conjunction with the accompanying following detailed description of preferred embodiment, it will help understand the present invention, wherein identical Reference represents identical part, wherein：
Fig. 1 shows the absorption pad with reference to paster, and it is applied to and is used together with endermically by material with ultrasonic signal In being delivered to patient, such as United States Patent (USP) 7, (little Bruce K thunder fourths) disclosed in 440,798.
Fig. 2 shows and shows for the chart of the percutaneous transfer rate of the difference of different commercially available pancreas islet prime forms.
Fig. 3 is the schematic diagram of application on human skin construction.
Fig. 4 is the schematic diagram of the ultrasonic medicinal induction system that waist is installed.
Fig. 5 is the schematic diagram of the ultrasonic medicinal induction system that arm is installed.
Fig. 6 is the design of the Frantz bottle for testing used in -1.
Fig. 7 is unit piece converter design.
Fig. 8 shows the component including 9 converters.
Fig. 9 shows that component includes 4 converters being fitted on stainless steel faceplate.
Figure 10 is alternation type ultrasonic transmission.
Figure 11 is identical with Fig. 2, but shows the uniformity of power level, supersonic frequency, and shows and excellent secrete woods (Humulin) and excellent secrete whether happy (Humalog) is used together with some type of converter assembly.
Figure 12 and Figure 13 are shown for the difference of transmission speed when the insulin of different model is excited via standard ultrasound.
Detailed description of the invention
It should be understood that in order to be more clearly understood from the present invention, having been simplified for the accompanying drawing of the present invention and the related elements of description； Meanwhile, for the sake of clarity, eliminate many other elements (or element) present in exemplary drug formulations and percutaneous biography Pass method and system.However, because these elements are not it is known in the art that and because these elements are contributed to the present invention Be best understood from, therefore these elements are not discussed in the present invention.Disclosure herein is related to known to those skilled in the art All of modification and change form.
It is applicant's understanding that in response to applications of ultrasound or ensonification, macromolecular formulation can be conveyed effectively.Fig. 1 shows One transdermal patch 100 for being adapted to be applied together with ultrasonic signal, wherein paster employs at least one absorption of absorbing material Pad or layer.Paster 100 is made up of framework material or backing material 10, and a region or cave are formed wherein.In shown enforcement In example, the cave accommodates a sound wave film 11.The sealing patch 300 of stripping film 12, until using.Stripping film 12 can be by arbitrary conjunction Suitable material is constituted, including but not limited to：The uvioresistant that can be obtained from the crystal X companies of Sha Lunxier (Pennsylvania) The polyethylene film (50 microns of thickness) of line, antistatic.In an illustrated embodiment, what is be oppositely arranged with sound wave film 11 is semi-permeable Property component 13.Semipermeability component 13 can adopt seperation film (membrance) or the film pressed close in function with user's skin (film) form.For example, paster can be fitted on skin, the so described directly contact skin of film 11.The inside of paster 100 It is absorption pad 14, absorption pad 14 preserves required material, for example, medicine or medical compounds 15.In an illustrated embodiment, Packing ring 16 is placed between framework material 10 and absorption pad 14.Packing ring 16 can be made up of arbitrary suitable material, such as synthetic rubber. Packing ring 16 forms reservoir or shrinkage pool, and absorption pad 14 is placed thereon.When being pressed against on skin, packing ring 16 forms barrier, and it becomes In prevent moisture and air paster flowing underneath and prevent disturb ultrasonic signal intensity.Selectively, sealant can be used Compound, ultrasonic gel or other suitable materials, for packing ring 16 or replacement packing ring 16, so as to provide around paster The sealing function on 100 borders prevents material or medicine from leaking from paster so as to provide moisture protection, and prevents air from patch Piece lower section enters.Certainly, in the case of without departing from invention disclosed herein purport, can to the part of paster 100 or construct into Row many variations.Additionally, except transdermal patch, the outside stimulus of ultrasound or other forms can also be in a similar manner used, with Just extraly or substitute transfer device on ultrasound, this includes but is not limited to bandage.
In outside stimulus, such as source of ultrasound signal, generally by (but being limited to) sound wave film 11, signal 110 is transferred to into patch On piece or other transfer devices with least one pad 14 or at least one absorbing material into.Be included at least one pad or Material 15 among at least one of which absorbing material, mutually should be released after ultrasonic signal shock.Then, material is from least one It is released in individual layers of absorbent material or at least one absorption pad, in certain embodiments through semipermeable membrane 13 and deposited Before, it is attached in living tissue, in living tissue or through living tissue, the living tissue can be but not limited to：Patient's skin The surface of skin 3.Although transfer device has been described as being used together with ultrasound 110, the form of other outside stimulus also may be used Additionally use outside ultrasound, or for substituting ultrasound.For example, be applied to living tissue (in some examples be skin) from Sub- electro-osmosis method, thermotherapy, radio wave, magnetic transmission laser, microwave signal, and/or electric current, are used as outside stimulus.For example, Ultrasonic signal is possibly used for being used together with iontherapy, or ultrasound can be used as the pretreatment of iontherapy application.
For the term " medicine ", " medical compounds ", " pharmaceutical active compounds " and " pharmaceutical preparation " of this paper, it should be understood that To use in a non-limiting manner, and only as explaining, because the present invention is applied to patient transmits many materials.Such as this paper institutes With " material " may include but be not limited to：Any material, solution or suspension, including but not limited to：Medicine or non-drug thing Matter, these materials can be by live body surface or live body film, and it is included but is not limited to：The live body film of living tissue and other forms.This The material of sample generally includes one or more active component and excipient.As used herein, " excipient " refers generally to for one kind Or for various active composition, as the material of diluent or carrier in medicine.Excipient is typically inert.Similar, Used herein is percutaneously non-limited way, and including intracutaneous (for example, skin conveying) and transmucosal (transmucosally) it is administered.
The pharmaceutical preparation and material preferred liquid form of percutaneous conveying.Liquid excipient is used as active ingredient carriers.For example, The material for percutaneously being conveyed generally can be made up of the active material in being suspended in liquid-carrier or adhesive.
Used as further embodiment, active material is normally immersed in excipient binder fluid, such as salt solution or acetic acid In salt (or ester) composition so that they are injectable.For example, insulin is usually placed in acetate (or ester) mixture. Ordinary matter and pharmaceutical liquid vehicle excipients include：Water, distilled water, buffered distilled water, acetate, salt solution, phosphate, Phosphate buffer, glycerine, saccharin, grapefruit flavours, methyl hydroxybenzoate, the P-hydroxybenzoic acid third of addition protein Ester, sodium acetate, fructose, glucose or sucrose, hydrogenated glucose syrups, mannitol, maltitol, sorbierite, xylitol, paddy egg In vain, tartrazines, peanut oil, sesame oil, beeswax, phenmethylol, BHA, Yoshinox BHT, octadecyl alcolol hexadecanol Mixture (including spermaceti and stearyl alcohol), chloreresol, ethylenediamine tetra-acetic acid (edta), ethylenediamine, essence, hydroxybenzoate salt are (right Hydroxybenzoic acid esters), imino group urea, isopropyl palmitate, n- (3- chlorallyls) hexa chloride (quaternary ammonium Salt 15), polysorbate, propane diols, sodium metabisulfite, lanolin and related substances, including sheep oil (lanolin) and become Brilliant solution.
Excipient generally comprises replacement component.For example, excipient potentially includes one or more preservative such as zinc, and One or more buffer such as disodium hydrogen phosphate.The present invention is based partially on following observation：Cucumber and pharmaceutical preparation are comprising suppression The mobility of active component processed so inhibition response sound it is saturating can transporting liquid carrier excipient and/or excipient ingredients. The present invention is based partially on following observation：Cucumber and pharmaceutical preparation include strengthening the transfer rate of the saturating active component of response sound Liquid carrier excipient and/or excipient ingredients.The present invention's is based partially on following observation：Cucumber and pharmaceutical preparation include Increase the liquid carrier excipient and/or excipient ingredients of the saturating active ingredient per unit time delivered volume of response sound.
Referring now to Fig. 2, two kinds of commercially available insulin-types are it illustrates to insonifying during response, the percutaneous transfer rate of human patientses Chart 200.Fig. 2 is represented, using the 125mW from foursquare 4 switch arrays, 30kHz ultrasonic signals, u100WithFor the data of the percutaneous transfer rate of human patientses.It has been discovered by the applicants that under transonic,ThanPercutaneously convey with bigger dosage at faster speed.This is due between two kinds of insulin-types Chemical change.It is excellent to secrete the basal insulin that woods is designed to slow effect, and excellent pleasure of secreting then is designed to Semilente Insulin, Jing Often take before the meal.
Table 1 showsWithBasis.
Table 1
Visible in table 1, the excellent Lin Heyou that secretes secretes differring primarily in that between happy insulin：A kind of preservative zinc oxide (gold Category preservative) amount increase and increase disodium hydrogen phosphate, phosphate is used as buffer.
High-visible from Fig. 2, under ultrasonic propagation, the transfer rate of insulin is in insulinWithType between change.Ultrasound is with metal interaction and can excite zinc compound, causes adding for metal ion Heat.
Fig. 2 is illustrated and excellent is secreted the comparison that Lin Heyou secretes transfer rate of the happy insulin under similar supersonic frequency and strength level. Using the element converter array of standard 4, to it is excellent secrete Lin Heyou and secrete the happy comparison through the transfer rate of skin of abdomen show, it is excellent to secrete woods For 0.98 unit/minute transfer rate, excellent secreting happy is 0.72 unit/minute transfer rate.Transmission flow difference be attributed to ultrasound and The difference of the interphase interaction of each component in targeted drug material.Secrete between pleasure in insulin load, tax in the excellent Lin Heyou that secretes There is little bit different in the preservative packaging of shape agent and employing.The interaction of ultrasound and these compositions, with different driving speed Whole pharmaceutical preparation is excited, and thus results in medicine through the faster or slower of the transfer rate of skin.All conditions identical In the case of, as shown in figure 11, wear human cadaver skin of abdomen it is excellent secrete woods transonic and be faster than excellent secrete pleasure.
The proportion that sodium dihydrogen phosphate has 1.67 (is higher than water, is insulin variantIn main medium).According to Speculate, this is the excellent influence factor for secreting happy transfer rate for slowing down response ultrasound.
As further non-limiting example, by compared with the ultrasonic conducting of compact medium be slower than by it is sparse or compared with Low dense material.Ultrasound is reflected and is transmitted energy and is obstructed by dense material.It is assumed that in the excellent presence high specific gravity secreted in pleasure Disodium hydrogen phosphate, which results in ultrasound and is obstructed, and thus slow down percutaneous conveying.
Experiment 1
In experiment 1, from the whole corpse of the mankind that intermountain organization center (Intermountain Tissue Center) obtains The sample of body skin of abdomen, the size of human sample (6.3) is diameter 2.25 ", 1 millimeter of thickness, positioned at fine by Vicell-9009 The absorption pad lower section of dimension element composition, in being placed in Frantz bottle (6.1), as shown in Figure 6.Supersonic source (6.5) be placed in absorption pad or It is clamped on cadaver skin sample (6.3) and downwards flask (6.2) top.
By a certain amount of insulin measured by standard insulin syringe (unit of standard 100), absorption is splined on Pad.
Next, the polyethylene film of 2.25 inch diameters and 0.156 mm of thickness is placed on into absorption pad or skin-like The top of product (6.3).
Supersonic source (6.5) is arranged on into the top of flask (6.2) and one below is may include：
(1) unit piece converter, as shown in Figure 7；
(2) array component being made up of 9 converters, as shown in Figure 8；
(3) the standard array component being made up of 4 converters being fixed on stainless steel faceplate, as shown in Figure 9；
(4) tinkertoy module, including 4 converters (as shown in Figure 9) being fixed on stainless steel faceplate and in original Another layer of converter is set on beginning layer.
Ultrasound is ordered about insulin and departs from absorption pad, and the sample for passing through human body skin, enters the receipts for collecting (6.6) Collection flask (6.4).Using the sample tap (6.5) of bottle (6.1) size, extract and collect medicine (6.6) for analyzing.
In experiment 1, unit piece converter as shown in Figure 7 is used for insulin, and the excellent of 100 units secretes woods or 100 lists The excellent of position secretes pleasure, in being delivered to Frantz bottle.Single switch element is piezoelectricity conversion crystal (7.1), and it is designed to electric energy Mechanical force is converted into, the piezoelectricity conversion crystal is coated with epoxy resin and is electrically connected in ultrasonic generation circuit.Supersonic frequency is 23- 30KHz,125mW/cm2Intensity.The duration of ultrasonic excitation is 1 minute, but experiment is carried out 10 times, and for excellent woods measure is secreted Average conveying be 14.7 units/per hour, secrete happy for 10.8 units/per hour for excellent.
Next, using the converter system corresponding to design as shown in Figure 9, in the configuration, by using conducting ring Oxygen tree fat (9.4) in stainless steel faceplate (9.3) and is electrically connected four piezo-electric crystals (9.2) are gluing, so that passing through The electric power that cable (9.1) sends electrically activates all crystalline tandems.The supersonic frequency of each converter is 23-30KHz, 125mW/cm2Intensity.Energy is always output as 4 × 125=500mW/cm2Intensity.
It is excellent to secrete happy result and be for the excellent result for secreting woods is 58.8 units/hour using the converter apparatus of Fig. 9 43.2 units/per hour.
Next, using the converter system corresponding to design as shown in Figure 8.In the configuration, 9 piezo-electric crystals (8.1) it is fixed on polymer embedding panel (8.3), and electrically connects, so that the electric power sent by cable (8.4) is by institute There is crystalline tandem formula to electrically activate.Converter (8.2) array is connected to ultrasound and produces circuit.The supersonic frequency of each converter is 23-30KHz,125mW/cm2Intensity.Energy is always output as 9 × 125=1,125mW/cm2Intensity.
It is excellent to secrete happy result and be for the excellent result for secreting woods is 105.8 units/hour using the converter apparatus of Fig. 9 77.76 unit/per hour.
Next, using the converter system corresponding to design as shown in Figure 9, but in the configuration, by another layer of tool There are four converters to be arranged on the original layers for being fixed on panel.With 8 piezo-electric crystals, 4 are located at the upper of bottom for the configuration Side.Each converter supersonic frequency is 23-30KHz, 125mW/cm2Intensity, energy is always output as 4 × 225=900mW/cm2 Intensity.
It is excellent to secrete happy knot for the excellent result for secreting woods is 70.56 units/hour using the stacked converter apparatus of Fig. 9 Fruit is 51.84 units/per hour.
As shown in Figure 10, wherein zig-zag continues 50 milliseconds to the ultrasound-transmissive for using in these experiments, immediately after Immediately equally continue 50 milliseconds of square waveform.The conversion of ultrasonic waveform contributes to preventing the cavitation in medicine or heating.
Table 2 confirms these discoveries, which show excellent secreting and happy secrete woods and conveyed with lower transfer rate than excellent.It is assumed that It is excellent secrete it is happy present in finer and close sodium dihydrogen phosphate ratio do not have the excellent of identical component to secrete woods and can faster pass through skin " wash-out " (elute) or diffusion.
Table 2
For the inspection of extra insulin preparation shows slower or very fast transfer rate.Figure 12 and 13 is observed including those As a result table.
For the different transfer rates of different insulin preparations observation indicate that, it may be necessary to as shown in Figure 4 and Figure 5 Ultrasonic transdermal drug delivery systems, be programmed based on the insulin transfer rate and combined standard ultrasonic signal that use.
In fig. 4 it is shown that the ultrasonic induction system of waist is installed on, wherein improving transdermal patch (4.3) is mounted with target It is in this example insulin to medicine, ultrasonic induction system is installed in the waist (4.4) of patient.Control device (4.1) To converter coupler (4.2), it forces insulin that the skin of patient is delivered to from paster to transmission electric signal, realizes ultrasonic pancreas islet Element transmission.
In fig. 5 it is shown that the ultrasonic induction system of arm is installed on, wherein improved transdermal patch (5.3) is mounted with Targeted drug, is in this example insulin, and ultrasonic induction system is installed on the arm of patient (5.6).Control device (5.1) be installed in paster (5.3) it is upper, remain in position near or over and by arm band (5.4).Control unit (5.1) electric signal is transmitted to being connected on the converter coupler of paster (5.3), it forces insulin to be delivered to patient from paster Skin, realize ultrasonic insulin transmission.
Summarize：
Substantially, sound transmission change in pharmaceutical carrier the related transport equation of excipient preparation used.
Further, disodium hydrogen phosphate isIn sodium ion source.Sodium ion positively charged.Excessive positive electricity The presence of lotus, can cause and interact comprising material opposite charge material in paster, and be inhaled by weak electrostatic attraction Attached or absorption is in which or on which.Perhaps, this hinders material (such as insulin) molecule to pass through solution from paster to skin and pass through skin Skin.Or, excessive positive charge may in itself interact with material, such as insulin molecule so that the subsequent quilt of the material Be adsorbed in paster material, or or even be adsorbed on skin biology can conversion coating, so as to slow down they be transported into it is living In skin or blood circulation.
Anyway, by the amount for reducing disodium hydrogen phosphate therein, can accelerate (may mix and absorb material from paster Material) (Fig. 1) in insulin and disodium hydrogen phosphate supersonic induced percutaneous transfer rate.It is assumed that by reducing wherein phosphoric acid The amount of disodium hydrogen changes the constituent of excipient solution with less metal and less preservative, also can similarly improve it His material, such as supersonic induced percutaneous transfer rate of other pharmaceutical preparations comprising other active components.Similarly, it is assumed that By the amount for reducing excipient ingredients more heavy than water, the supersonic induced Jing of the medicine of material such as insulin-containing can be improved Skin transfer rate.Similarly, also speculate and arrive, by main using the excipient ingredients containing the proportion less than 1.67, thing can be increased The supersonic induced percutaneous transfer rate of the medicine of matter such as insulin-containing.
It should be understood that as medicine and other materials are prepared by traditional handicraft, the disodium hydrogen phosphate with decrement, the ratio of decrement Great excipient ingredients and/or the medicine for reconfiguring and thing of the main excipient ingredients using proportion less than 1.67 in water Matter, may also be employed process similarity.
According to an aspect of the present invention, the good candidate as the percutaneous conveying of ultrasound can be identified with similar standard Material, or preparation is re-started to percutaneous conveying.For example, can prepare or obtain the list of material and correspondent composition.Have Less than the excipient ingredients of 1.67 proportions and/or without disodium hydrogen phosphate and/or with the excipient component being close to the proportion of water Material, all can be used as the good candidate material of supersonic induced percutaneous conveying.Similarly, with proportion approximately or higher than 1.67 Excipient ingredients, and/or comprising disodium hydrogen phosphate, the weak suction for preparing supersonic induced percutaneous conveying again may be selected as The candidate substances of gravitation.The candidate substances predicted have the ultrasonic Jing of higher active component than the candidate substances of weak attraction Skin inductivity is higher, and they have identical active component.Further non-limiting example, for from the corresponding ultrasound sound of paster For the rapid transdermal transfer rate of process,The good candidate substances of the first kind can be divided into, andCan Equations of The Second Kind can be divided into, as less attractive candidate substances.
The part of the present invention is also based on following observation：Cucumber and pharmaceutical preparation comprising liquid carrier excipient and/or Excipient ingredients comprising sodium (such as but not limited to salt solution), increased the saturating transfer rate of active component response sound and cause more Large compound can thoroughly be conveyed in response to sound.The present invention's is based partially on following observation：Cucumber and pharmaceutical preparation are included Liquid carrier excipient and/or the excipient ingredients comprising disodium hydrogen phosphate, when increased the saturating unit of active component response sound Between delivered volume and more large compound is conveyed thoroughly in response to sound.
Although the application is used for the deformation of different insulin, it should be noted that for ultrasonic transdermal drug conveying Other drugs product also will similarly need to test ultraphonic agent amount transport property.In fact, the method can be used to lead to Overweight freshly prepared excipient carrier composition, reconfigures medicine to make it easier for ultrasound-transmissive.
One embodiment of the present of invention is a kind of raising active component in the material prepared according to phosphoric acid disodium hydrogen formula The method of the saturating percutaneous penetrance of middle response sound, it includes：The amount of the disodium hydrogen phosphate in formula is reduced to provide phosphoric acid hydrogen two The preparation that sodium is reduced；And the formula reduced according to disodium hydrogen phosphate, prepare the material.In certain embodiments, the thing Matter further includes insulin.In certain embodiments, described sound includes that ultrasonic sound is saturating thoroughly.In certain embodiments, it is described The amount of reduction disodium hydrogen phosphate include substituting the disodium hydrogen phosphate with the composition with proportion less than 1.67.In some enforcements Example, described reduction includes that the component for being about water with proportion substitutes the disodium hydrogen phosphate.
One embodiment of the present of invention is a kind of for being suitable for the prediction of the supersonic induced material for being percutaneously delivered to patient The method that property is classified, methods described includes：A) determine the material whether comprising disodium hydrogen phosphate；And if b) including, The material is divided into into Equations of The Second Kind；And c) if it did not, the material is divided into into the first kind；D) the wherein described first kind The material of the percutaneous transfer rate with relatively high prediction is belonged to, and described Equations of The Second Kind belongs to the Jing with relatively low prediction The material of skin transfer rate.In certain embodiments, the list that material is provided is further included, wherein for each in the list Material, is determined as above and is classified.
One embodiment of the present of invention is a kind of by changing with the excipient solution or carrier of active component so as to carry The method that active component is percutaneously conveyed in high material, so that when being used together with ultrasonic medicinal induction system, producing higher Percutaneous transfer rate.
One embodiment of the present of invention is a kind of ultrasonic induction system for transmitting medicine, and it is adopted including at least one The transdermal patch of absorption pad, it is connected to single switch or switch array component, and is controlled by wearable device, wherein Ultrasound is transmitted and dosage is passed to into patient by loading the paster of medicine.In certain embodiments, system is installed on patient's On arm.In certain embodiments, system is installed on the waist of patient.In certain embodiments, described ultrasonic transmission can be Standard sine waveform version.In certain embodiments, described ultrasonic transmission can be the combination of ultrasonic waveform.
One embodiment of the present of invention is a kind of ultrasonic conveying device for transmitting medicine, and it is adopted including rare one The transdermal patch of absorption pad, it is connected to single switch or switch array component, and is controlled by wearable device, wherein Ultrasound is transmitted and dosage is passed to into patient by loading the paster of medicine, wherein using alternation type (or alternate type) ultrasonic waveform Transmission, to avoid cavitation or overheated to medicine or patient skin.
It will be evident for a person skilled in the art that in the situation without departing from the spirit or scope of the present invention Under, apparatus and method of the present invention can be modified and be deformed.It is contemplated that cover the modification of the present invention and change form, As long as they are in the range of claim and its equivalent form of value.

Claims (19)

1. it is a kind of to improve active component saturating percutaneous penetrance of response sound in the material prepared according to phosphoric acid disodium hydrogen formula Method, it is characterised in that it includes：
A) amount of the disodium hydrogen phosphate in formula is reduced, to provide the formula of disodium hydrogen phosphate reduction；With
B) formula reduced according to disodium hydrogen phosphate, prepares the material.
2. method according to claim 1, it is characterised in that described material further includes insulin.
3. method according to claim 2, it is characterised in that described sound includes that ultrasonic sound is saturating thoroughly.
4. method according to claim 1, it is characterised in that described reduction include with proportion less than 1.67 into Divide and substitute the disodium hydrogen phosphate.
5. method according to claim 1, it is characterised in that described reduction includes that the component for being about water with proportion is substituted The disodium hydrogen phosphate.
6. it is a kind of to improve active component saturating percutaneous penetrance of response sound in the material prepared according to the formula comprising excipient Method, wherein the excipient include it is at least one be at least about containing proportion 1.67 component, methods described includes：
A) amount that proportion is at least about 1.67 excipient ingredients is reduced, to provide the second formula；With；
B) according to the described second formula, the material is prepared.
7. method according to claim 6, it is characterised in that at least one active component includes insulin.
8. method according to claim 7, it is characterised in that the sound includes that ultrasonic sound is saturating thoroughly.
9. method according to claim 7, it is characterised in that the reduction excipient component includes：With with few The excipient component of at least about 1.67 proportions is substituted in the component of 1.67 proportions.
10. method according to claim 7, it is characterised in that described reduction includes：With the group with about water proportion Divide the excipient component for substituting at least about 1.67 proportions.
A kind of 11. methods for being classified to the prediction applicability of the supersonic induced material for being percutaneously delivered to patient, it is special Levy and be, including：
A) determine material whether comprising disodium hydrogen phosphate；And
If b) including the material is divided into into Equations of The Second Kind；With
C) if it did not, the material is divided into into the first kind；
D) the wherein described first kind belongs to the material of the percutaneous transfer rate with relatively high prediction, and described Equations of The Second Kind is returned Belong to the material of the percutaneous transfer rate with relatively low prediction.
12. methods according to claim 11, it is characterised in that further include：For each material in list, carry out Described determination and classification.
13. it is a kind of for improving material in active component percutaneous described method, it is characterised in that methods described is by changing With the excipient solution or carrier of active component, so that when being used together with ultrasonic medicinal induction system, producing higher Percutaneous transporting velocity.
14. a kind of ultrasonic induction systems for conveying medicine, it is characterised in that the system is adopted includes the percutaneous of absorption pad Paster, it is connected to single switch or switch array component, and is controlled by wearable device, wherein ultrasound is by loading Dosage is simultaneously conveyed to patient by the paster transmission of medicine.
The 15. ultrasonic induction systems for conveying medicine according to claim 14, it is characterised in that the system is installed On the arm of patient.
The 16. ultrasonic induction systems for conveying medicine according to claim 14, it is characterised in that the system is installed In the waist of patient.
17. the ultrasonic induction system for conveying medicine according to claim 14, it is characterised in that described ultrasound biography Passing can transmit for the ultrasonic wave of standard sine waveform.
The 18. ultrasonic induction systems for transmitting medicine according to claim 14, it is characterised in that described ultrasound biography Pass to be the combination of ultrasonic waveform.
19. a kind of ultrasonic conveying devices for conveying medicine, it is characterised in that the system is adopted includes the percutaneous of absorption pad Paster, it is connected to single switch or switch array component, and is controlled by wearable device, wherein ultrasound is by loading Dosage is simultaneously conveyed to patient by the paster transmission of medicine, wherein transmitted using alternation type ultrasonic waveform, to avoid cavitation or to medicine Thing or patient skin are overheated.
CN201580036489.0A 2014-07-09 2015-07-09 Modification of pharmaceutical preparations to make them more conducive to ultrasonic transdermal delivery Pending CN106604723A (en)

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US201461998790P 2014-07-09 2014-07-09
US201461998788P 2014-07-09 2014-07-09
US61/998,790 2014-07-09
US61/998,788 2014-07-09
US201461999589P 2014-08-01 2014-08-01
US61/999,589 2014-08-01
US201562125837P 2015-02-02 2015-02-02
US62/125,837 2015-02-02
USPCT/US2015/039268 2015-07-06
USPCT/US2015/039264 2015-07-06
US2015039272 2015-07-06
USPCT/US2015/039236 2015-07-06
US2015039268 2015-07-06
USPCT/US2015/039272 2015-07-06
US2015039236 2015-07-06
US2015039264 2015-07-06
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Citations (3)

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US20060188556A1 (en) * 2005-02-24 2006-08-24 Redding Bruce K Ultrasonically assisted dermal or transdermal delivery substance preparation
WO2012129545A1 (en) * 2011-03-23 2012-09-27 Redding Bruce K Systems and methods for enhancing the delivery of compounds to skin pores using ultrasonic waveforms

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CA2552690C (en) * 2002-12-31 2014-12-09 Ultra-Sonic Technologies, L.L.C. Transdermal delivery using encapsulated agent activated by ultrasound and/or heat

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050075599A1 (en) * 2001-08-24 2005-04-07 Redding Bruce K. Ultrasonically enhanced saline treatment for burn damaged skin
US20060188556A1 (en) * 2005-02-24 2006-08-24 Redding Bruce K Ultrasonically assisted dermal or transdermal delivery substance preparation
WO2012129545A1 (en) * 2011-03-23 2012-09-27 Redding Bruce K Systems and methods for enhancing the delivery of compounds to skin pores using ultrasonic waveforms

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Correction item: Priority

Correct: 61/998,788 2014.07.09 US|61/998,790 2014.07.09 US|61/999,589 2014.08.01 US|62/125,837 2015.02.02 US|PCT/US2015/039236 2015.07.06 US|PCT/US2015/039268 2015.07.06 US|PCT/US2015/039264 2015.07.06 US|PCT/US2015/039272 2015.07.06 US

False: 61/998,788 2014.07.09 US|61/998,790 2014.07.09 US|61/999,589 2014.08.01 US|62/125,837 2015.02.02 US|PCT/US2015/039236 2015.07.06 US|PCT/US2015/039268 2015.07.06 US

Number: 17

Volume: 33

CI02 Correction of invention patent application
CI02 Correction of invention patent application

Correction item: Priority

Correct: 61/998,788 2014.07.09 US|61/998,790 2014.07.09 US|61/999,589 2014.08.01 US|62/125,837 2015.02.02 US|PCT/US2015/039236 2015.07.06 US|PCT/US2015/039268 2015.07.06 US|PCT/US2015/039264 2015.07.06 US|PCT/US2015/039272 2015.07.06 US

False: 61/998,788 2014.07.09 US|61/998,790 2014.07.09 US|61/999,589 2014.08.01 US|62/125,837 2015.02.02 US|PCT/US2015/039236 2015.07.06 US|PCT/US2015/039268 2015.07.06 US

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Application publication date: 20170426