WO2015122838A1 - Rapidly dissolvable microneedles with drug-impregnated tips - Google Patents
Rapidly dissolvable microneedles with drug-impregnated tips Download PDFInfo
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- WO2015122838A1 WO2015122838A1 PCT/SG2014/000058 SG2014000058W WO2015122838A1 WO 2015122838 A1 WO2015122838 A1 WO 2015122838A1 SG 2014000058 W SG2014000058 W SG 2014000058W WO 2015122838 A1 WO2015122838 A1 WO 2015122838A1
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- microneedle
- microneedles
- skin
- rapidly dissolvable
- drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0061—Methods for using microneedles
Definitions
- TITLE RAPIDLY DISSOLVABLE MICRONEEDLES WITH DRUG- IMPREGNATED TIPS
- the present invention relates generally to transdermal drug delivery, and particularly to transdermal drug delivery of active pharmaceutical ingredients and biologies using rapidly dissolvable microneedles. More specifically, the present invention relates to rapid delivery of active pharmaceutical ingredients for the purposes of vaccination, screening of tuberculosis, diagnosis and treatment of hypersensitivity, allergic skin testing, etc.
- TDD Transdermal drug delivery
- an adhesive patch with a matrix layer that is loaded with a drug with high concentration.
- the high concentration gradient between the matrix layer and the skin provides a diffusion pressure for the drug residing in the matrix layer to move to the skin.
- the typical TDD is able to only deliver small molecular drugs across the skin. Currendy there are a number of drugs that are approved by US FDA for transdermal delivery, and they are normally limited to small molecular drugs. Contemporary drugs such as peptides, hormones, vaccines and other biologies which normally have large molecular size cannot get through the skin via diffusion mode.
- Microneedles have been invented in the 1970s to overcome the molecular size problem.
- microneedles of lOOum to 500um length will breach the skin by creating micro- holes on the skin, providing a pathway for the big molecular drugs to enter the skin.
- the penetration depth is superficial, i.e. lOOum to 200um under the skin, the microneedles do not reach the nerve ends and therefore the use of microneedles are quite pain-free.
- the first method is via injection of liquid drugs using hollow microneedles and the second method is via insertion of solid drugs using solid micronneedles.
- the injection of liquid drugs normally requires the needles to penetrate deeper so that the liquid can be injected and can stay in the skin without spilling out of the skin.
- the hollow microneedles are inserted e.g. 900um under the skin, a volume of lOul per hollow microneedle has to be injected over a length of time to avoid spilling out because the drug takes time to diffuse into the skin.
- the needle size is also much larger because of the lumen for liquid injection; for example, for a lOOum lumen, the size of a hollow microneedle has to be at least 200um or more.
- the increase in size and penetration depth increases the pain and the duration needed to deliver a 0.5ml volume of drug spans from 15 minutes to 30 minutes.
- solid microneedles are much smaller in size, typically 50um to lOOum in size and 300um to 500um in length. They are normally painless in these dimensions.
- drugs are coated on the surface of the solid microneedles. This poses a great issue in dose quantification because although the quantity loaded onto the microneedles can be determined, the dose that is delivered to the skin finally cannot be determined because some of the coated drug will stay outside the skin during the insertion process.
- US patents 7,537,795B2, 7,556,821 B2 and 7,963,935B2 awarded to Alza Corp. use such coating technique for their solid microneedles.
- microneedles which are made of dissolvable materials mixed with the drugs and which deliver drugs by penetrating and dissolving in the skin.
- this dissolvable configuration no drugs are coated on the needle surface so no drug will peel off and stay outside the skin during the insertion process.
- the penetration depth is normally much less than the full length of the needles due to the elastic and stretchy nature of the skin.
- 500um microneedles will only have a penetration depth of 250um - 300um.
- each microneedle will have different penetration depth and therefore different dose delivery, which eventually leads to unquantifiable dose.
- dissolvable microneedles Another critical issue in dissolvable microneedles is the dissolving time.
- the dissolvable material used is hyaluronic acid (HA), which has molecular weight of 5,000— 20,000,000 Da. Long duration is required for the HA to dissolve in the skin after penetration. The typical dissolving duration required is half an hour to an hour, which may be too long for most medical applications such as hypersensitivity diagnosis and treatment, vaccination, and allergic skin testing. Hence, rapid delivery of active pharmaceutical ingredients such as antigens, hormones, vaccines and other drugs by microneedles are highly desirable.
- HA hyaluronic acid
- the present invention involves a drug patch of rapidly dissolvable microneedles comprising needle tips that are impregnated with drugs and the use " of the rapidly dissolvable microneedles for delivering drugs transdermally.
- the rapidly dissolvable microneedle patch 10 comprises a plurality of microneedles or tiny spikes 20 which are disposed on a back layer 30.
- the microneedles 20 have tapered geometry and have two parts on each microneedle 20, namely the drug tip 22 and the needle body 24.
- the drug tip 22, which occupies only a fraction of the volume of the apex of the microneedle, contains active pharmaceutical ingredients which are impregnated into the microneedle by centrifuging.
- the penetration line 26 is an imaginary line dividing the inserted portion 32 of the microneedle 20 (inserted into the skin) and the non-inserted portion 34 of the microneedle 20 when the microneedle 20 is inserted into the skin.
- the inserted portion 32 extends from the apex 28 of the microneedle to the penetration line 26, and the non-inserted portion 34 extends from the penetration line 26 to the base 29 of the microneedle. In this way, the drug tip 22 which stays within the inserted portion 32 of the microneedle 20 is guaranteed to be fully delivered to the skin.
- the present invention also includes a fabrication method for making rapidly dissolvable microneedles with tips that are impregnated with drugs.
- a master mould 100 of metal microneedle array is fabricated.
- Microneedle templates 200 are duplicated from the master mould 100 via conventional techniques such as injection moulding of liquid silicone rubber, room temperature vulcanizing (RTV) silicone casting, and plastic injection moulding.
- drug in liquid form is dispensed into the cavities 220 on microneedle templates 200 and the templates are spun using a centrifuge until the excipients are vaporized. The spinning will ensure that the drug fills up the cavity completely and forms drug tips 240.
- the dissolvable material such as micro-hyaluronic acid at various concentrations is dispensed on the templates 200 and spun briefly using a centrifuge to form the needle body 260 and the back layer 280.
- the present invention covers a method for applying a rapidly dissolvable microneedle patch 540 and delivering full dose to the skin 560 reliably.
- the method involves tensioning the skin by a transparent compression ring 520 and rapidly inserting the rapidly dissolvable microneedles 580 into the skin 560 and subsequently pressing the patch 540 against the skin 560 for the dissolving duration.
- the active pharmaceutical ingredient which is always impregnated within the penetration line is inserted fully into the skin for ensuring complete dose delivery.
- Fig. 1 is the perspective view of the rapidly dissolvable microneedle patch
- Fig. 2 is the close-up view of the rapidly dissolvable microneedle showing the drug- impregnated tip and the needle body
- Fig. 3 is the preferred packaging configuration of the rapidly dissolvable microneedle patch
- Fig. 4 is a schematic diagram showing the process flow for making rapidly dissolvable micronneedles with drug-impregnated tips
- Fig. 5 (a)— (d) are schematic diagrams showing the penetration steps of the rapidly dissolvable microneedles which leads to complete dose delivery
- Fig. 6 (a) and (b) are photographs of the rapidly dissolvable microneedles before and after skin penetration, showing complete dose delivery
- Dissolvable microneedles are developed recently to address several issues of the dry-coated solid microneedles. Apart from the fact that the coated drug can be peeled off easily from the needle surface during the insertion process, drug loading of the solid microneedles (i.e. the amount of the drug coat-able on the needle surface) remains a great drawback. There are attempts where excessive drugs are coated on the needle surface until the drug forms a lump on the needle surface. The lump forms an irregular surface that hinders the insertion of the microneedles into the skin and normally will fall off the surface before penetrating into the skin.
- drugs are impregnated into dissolvable microneedles so there is no alien, irregular lump to adhere on the needle surface which is prone to falling off the surface before penetrating into the skin.
- the amount of drug that can be loaded into a needle increases 10 to 100 folds.
- dissolvable microneedles still need to address.
- the characteristics of the dissolvable material have to be such that it is dissolvable upon contact with skin but it should be moist and heat resistant for transportation and storage.
- the material has to also provide sufficient hardness for effective penetration.
- the materials used for making dissolvable microneedles are either too soft (e.g. sucrose, poly-lactic acid (PLA) or Poly- (Ethylene Glycol) Diacrylate (PEGDA), too susceptible to moist (e.g. PVP), or take too long to dissolve (e.g. hyaluronic acid by Cosmed which is 5,000— 20,000,00 kDa in size).
- the present invention involves a patch of rapidly dissolvable microneedles comprising tips that are impregnated with drugs and the use of the rapidly dissolvable microneedles for delivering drugs transdermally.
- Figure 1 shows the preferred embodiment of a rapidly dissolvable microneedle patch that contains tips impregnated with drugs.
- the rapidly dissolvable microneedle patch 10 comprises a plurality of microneedles or tiny spikes (or microneedles) 20 which are disposed on a back layer 30.
- the microneedles 20 have tapered geometry such as but not limited to pyramidal or conical shape and have two parts on each microneedle 20, namely the drug tip 22 and the needle body 24.
- the drug tip 22 occupies only a fraction of the volume of a microneedle.
- the drug tips 22 are formed by vaporizing a liquid drug using a centrifuge to dehydrate the drug to reduce the volume.
- the liquid drug can be vaccines, hormones, peptides and other biologies.
- the drug tips 22 normally span 50um to lOOum from the tip and do not occupy more than 5% of the total volume of the microneedle.
- the needle body 24 and the back layer 30 are made from dissolvable material such as chitosan, micro-hyaluronic acid, and hydrogels.
- the drug tip 22 may have a length of OOum from the tip and the needle body 24 may have 400um - 500um length from the drug tips 22.
- the drug tips 22 have a tip size of 5um to lOum and the needle body 24 has a square base of 150um to 200um.
- the back layer 30 has a thickness of 0.5mm to 2mm.
- the needle body 24 and the back layer 30 can be made with the same material or they can be made with different materials.
- a microneedle when inserted into the skin has two portions, one which is inserted into the skin and dissolves and another one which stays out of the skin and does not dissolve. It is very critical to identify penetration depth so that the drugs can be impregnated only within the inserted portion. So, a penetration line 26 is an imaginary line dividing the inserted portion 32 of the microneedle 20 (inserted into the skin) and the non- inserted portion 34 of the microneedle 20 when the microneedle 20 is inserted into the skin.
- the inserted portion 32 extends from the apex 28 of the microneedle to the penetration line 26, and the non-inserted portion 34 extends from the penetration line 26 to the base 29 of the microneedle. In this way, the drug tip 22 which stays within the inserted portion 32 of the microneedle 20 is guaranteed to be fully delivered to the skin.
- Figure 2 shows a close-up view of one rapidly dissolvable microneedle 40, comprising the drug tip 22, needle body 24, an imaginary penetration line 26 and the back layer 30.
- the drug tip 22 is made of drug which spans from the apex of the microneedle.
- the penetration line 26 is an imaginary line separating the penetrated portion (or the dissolved portion) 32 of the rapidly dissolvable microneedle 40 (inserted into the skin 34) and the un-penetrated portion (or the remaining portion) 36 of the rapidly dissolvable microneedle 40 when it is inserted into the skin 34.
- the drug tip 22 is always kept within the penetration line 26 so that it is always fully inserted into the skin 34.
- the depth or distance of the penetration line 26 from the apex is determined by various factors, including the length of the microneedle, the insertion, force and speed, the geometry and sharpness of the microneedles, the mechanical strength of the material, the hygroscopic and most importantly, the wear time or dissolving duration of the rapidly dissolvable microneedle. For example, with roughly lm/s insertion speed and 0.1 N insertion force, a 600um tall rapidly dissolvable microneedle made with uHA may dissolve 200um for a wear time of 10 seconds. In this case, the penetration line 26 is 200um deep from the apex and the drug tip 22 can be as long as 200um from the apex.
- a drug of hepatitis B vaccine which has a volume of 0.3ml and which contains lOug of antigens can be impregnated into the rapidly dissolvable microneedle 40 and form the drug tip 22, and micro-hyaluronic acid (uELA) with molecular weight between 3— 10 kDa can be used to form the needle body 24 and the back layer 30.
- uHA micro-hyaluronic acid
- Figure 3 shows a preferred packaging configuration 50 comprising a transparent casing 60, and a sealing film 70.
- the transparent casing further comprises a sealing surface 52 onto which the sealing film 70 will be affixed, a first compartment 54 immediately following the sealing surface 52 for receiving the back layer 30 of the microneedle patch, and a second compartment 56 which is smaller and immediately underneath the first compartment 54 for receiving the microneedles 20, and a flat surface 58 between the two compartments acting as a seat for the back layer 30.
- the transparent casing 60 may be thermo-formed, injection moulded or machined.
- the sealing film 70 may be made of insulating material such as polymer or aluminum which may be affixed to the sealing surface 52 of the transparent casing 60 via pressure- or heat-sensitive adhesive.
- the advantages for a rapidly dissolvable microneedle patch are namely 1) it is painless; 2) it dissolves instantly so it is suitable for replacing parenteral (injection) drug adrninistration; 3) it deliver drugs precisely into the epidermal layer (200um - 300um below stratum corneum), this is ideal for point-of-care diagnostic skin tests such as tuberculosis, hypersensitivity and allergy which currently rely on Mantoux technique (extremely painful), which injects 0.1ml of liquid drug intradermally; 4) the active pharmaceutical ingredients can be preserved by the sugars so cold chain is not required for the transportation and storage of the microneedle patches.
- the potential uses of the present invention are vaccination, diagnosis and treatment of hypersensitivity and allergy, and tuberculosis point-of-care diagnostic tests. Fabrication of Rapidly Dissolvable Microneedles with Drug-Impregnated Tips
- Figure 4 shows a schematic diagram of the flow of the fabrication process.
- a microneedle master mould 100 comprising the desired microneedle geometry and array size is fabricated.
- the fabrication technique can range from grinding, to precision wire cutting, to micro fabrication processes, which are well known in the art.
- a moulding material is cast over the master mould 100 to form a template 200 which comprises the negative shape of the master mould 100.
- a suitable moulding material is typically silicone with various hardness indices, and the choice of material is not limited to silicone.
- a person skilled in the art will have the knowledge in determining a suitable material to form the template.
- active pharmaceutical ingredient (API) 300 which includes but not limited to vaccines, hormones, antigens, antibodies, peptides and other biologies, can be spotted onto the template cavities 220 and the template 200 is subjected to a centrifugal process, normally but not limited to 3,000— 5,000 rpm spinning for 30— 300 seconds.
- the centrifugal process ensures that the template cavities 220 are completely filled up by the active pharmaceutical ingredient (API) 300 and that the excipient of the active pharmaceutical ingredient (API) 300.
- the active pharmaceutical ingredient (API) 300 may be pre-mixed with a strengthening substance such as polyethylene glycol diacrylate (PEGDA), polyvinylpyrrolidone (PVP), micro-hyaluronic acid ( ⁇ ), which has a molecular size of 3— 5 kDa, and so on.
- PEGDA polyethylene glycol diacrylate
- PVP polyvinylpyrrolidone
- ⁇ micro-hyaluronic acid
- the mixing can be achieved by first spotting the strengthening substance into the template cavities 220 and subjecting the template 200 to a centrifugal process, and then immediately spotting the active pharmaceutical ingredient (API) 300 into the template cavities 220 and subjecting the template 200 to a second centrifuging process, which mixes the strengthening substance and the active pharmaceutical ingredient (API) 300. Subsequently, the same strengthening substance or a new substance can be added onto the template 200 to form the rest of the microneedle body 260 and the back layer 280 of the microneedle patch. The template 200 is subjected to another centrifugal process to ensure complete fusion of the drug- impregnated tips 240 with the microneedle body 260 and the back layer 280.
- micro-hyaluronic acid ( ⁇ ) with molecular size of 3,000 - 5,000 Da has several unique characteristics that make it the ideal candidate fo the strengthening substance: (1) it provides sufficient mechanical strength for effective skin penetration; (2) it dissolves instantly when made in contact with the skin; (3) it exhibits excellent moist and temperature resistance which are vital for transportation and storage. It is obvious that other rapidly dissolvable materials which provide sufficient mechanical strength can also be used to make rapidly dissolvable microneedles. Other potential materials are chitosan, PVP, PEDGA, and other smart polymers.
- Complete dose delivery is vital for drug delivery effectiveness.
- Current microneedle patches coat the drug load on the surface of the microneedles and a portion of the drug load will inevitably stay outside of the skin during the penetration process. Incomplete delivery is the largest hindrance to having consistent clinical trial results. Since our drug load is impregnated into the tips of our rapidly dissolvable microneedles, we have found a solution to overcome this critical issue.
- a microneedle applicator 500 with a transparent skin tensioning ring 520 which is loaded with a rapidly dissolvable microneedle patch 540, is compressed onto a skin site 560.
- the preferred skin sites are but not limited to outer upper arms, inner and outer lower arms, and stomachs.
- the compression force provided through the transparent skin tensioning ring 520 is between 0.1N - 1.0N such that the skin site 560 is sufficiently tensioned (stretched) and fixed.
- the transparent skin tensioning ring 520 is held with the compression force onto the skin throughout the application procedure.
- the rapidly dissolvable microneedle patch 540 is inserted into the skin at the predetermined speed, e.g. lm/s - 6m.s.
- the predetermined speed e.g. lm/s - 6m.s.
- the insertion speed is normally provided by a spring (not shown).
- the insertion of microneedles 540 is not full length; only 200um - 300um of the microneedles will be inserted into the skin normally.
- the skin site 560 When inserted, the skin site 560 will form a penetration line 600 that separates the inserted portion of the microneedles 620 and non-inserted portion of the microneedles 640.
- the penetration line 600 coincides with the penetration depth, which is 200um— 300um from the apex 660 of the microneedles 580.
- active pharmaceutical ingredients are impregnated between the apex 660 of the microneedles 580 and the penetration line 600.
- the inserted portion of the microneedles 620 starts to dissolve instantly. It is very important to hold the inserted portion of the microneedles 620 in the skin site 560 so that the dissolving can be completed, normally within 10 seconds to one minute. Therefore, there is a holding force of 0.1 N - 1.0N to hold the inserted portion of the microneedles 620 in the skin site 560 for the dissolving duration.
- the holding force is normally provided by the same spring (not shown) that provides the insertion speed-. The holding and the dissolving of the inserted portion of microneedles 620 and is shown in Fig. 5(c).
- the applicator 500 as well as the non-inserted portion of the microneedles 640 are removed from the skin site 560 and the inserted or dissolved portion of the microneedles 620 remain in the skin site 560.
- FIG. 6(a) shows a rapidly dissolvable microneedle patch comprising tips impregnated with blue dye.
- the blue dye was impregnated within the apex of the microneedles and the penetration line, or more particularly, within lOOum from the apex.
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Abstract
The present invention relates to rapidly dissolvable microneedles comprising drug-impregnated tips, the medical use thereof. In the preferred embodiment, the rapidly dissolvable microneedle patch (10) comprises a plurality of microneedles or tiny spikes (20) which are disposed on a back layer (30). The microneedles (20) have tapered geometry and have two parts on each microneedle (20), namely the drug tip (22) and the needle body (24). The drug tip (22), which occupies only a fraction of the volume of the apex of the microneedle, contains active pharmaceutical ingredients which are impregnated into the microneedle by centrifuging. In practice, only a portion of the microneedle (20) will be inserted into the skin. The penetration line (26) is an imaginary line dividing the inserted portion (32) of the microneedle (20) (inserted into the skin) and the non-inserted portion (34) of the microneedle (20) when the microneedle (20) is inserted into the skin. The inserted portion (32) extends from the apex (28) of the microneedle to the penetration line (26), and the non- inserted portion (34) extends from the penetration line (26) to the base (29) of the microneedle. In this way, the drug tip (22) which stays within the inserted portion (32) of the microneedle (20) is guaranteed to be fully delivered to the skin.
Description
TITLE: RAPIDLY DISSOLVABLE MICRONEEDLES WITH DRUG- IMPREGNATED TIPS
BACKGROUND
Field of the Invention
The present invention relates generally to transdermal drug delivery, and particularly to transdermal drug delivery of active pharmaceutical ingredients and biologies using rapidly dissolvable microneedles. More specifically, the present invention relates to rapid delivery of active pharmaceutical ingredients for the purposes of vaccination, screening of tuberculosis, diagnosis and treatment of hypersensitivity, allergic skin testing, etc.
Background of the Invention
Transdermal drug delivery (TDD) remains a common method to administer drugs to the body. TDD is carried out with an adhesive patch with a matrix layer that is loaded with a drug with high concentration. The high concentration gradient between the matrix layer and the skin provides a diffusion pressure for the drug residing in the matrix layer to move to the skin. The typical TDD is able to only deliver small molecular drugs across the skin. Currendy there are a number of drugs that are approved by US FDA for transdermal delivery, and they are normally limited to small molecular drugs. Contemporary drugs such as peptides, hormones, vaccines and other biologies which normally have large molecular size cannot get through the skin via diffusion mode.
Microneedles have been invented in the 1970s to overcome the molecular size problem. In a practical mode, microneedles of lOOum to 500um length will breach the skin by creating micro- holes on the skin, providing a pathway for the big molecular drugs to enter the skin. And since the penetration depth is superficial, i.e. lOOum to 200um under the skin, the microneedles do not reach the nerve ends and therefore the use of microneedles are quite pain-free. There are many other advantages of drug delivery by microneedles in addition to pain free injection, such as avoidance of gastro-intestinal tract (digestion of drugs), avoidance of cold-chain (drugs are dry- deposited and preserved by sugar), and ease of use (home use).
There are two general methods to dehver drugs to the skin using microneedles, the first method is via injection of liquid drugs using hollow microneedles and the second method is via insertion of solid drugs using solid micronneedles. The injection of liquid drugs normally requires the needles to penetrate deeper so that the liquid can be injected and can stay in the skin without spilling out of the skin. Even though the hollow microneedles are inserted e.g. 900um under the skin, a volume of lOul per hollow microneedle has to be injected over a length of time to avoid spilling out because the drug takes time to diffuse into the skin. The needle size is also much larger because of the lumen for liquid injection; for example, for a lOOum lumen, the size of a hollow microneedle has to be at least 200um or more. The increase in size and penetration depth increases the pain and the duration needed to deliver a 0.5ml volume of drug spans from 15 minutes to 30 minutes. These are the disadvantages of the hollow microneedles.
On the other hand, solid microneedles are much smaller in size, typically 50um to lOOum in size and 300um to 500um in length. They are normally painless in these dimensions. In solid microneedle configurations, drugs are coated on the surface of the solid microneedles. This poses a great issue in dose quantification because although the quantity loaded onto the microneedles can be determined, the dose that is delivered to the skin finally cannot be determined because some of the coated drug will stay outside the skin during the insertion process. US patents 7,537,795B2, 7,556,821 B2 and 7,963,935B2 awarded to Alza Corp. use such coating technique for their solid microneedles.
Recently there are solid microneedles which are made of dissolvable materials mixed with the drugs and which deliver drugs by penetrating and dissolving in the skin. In this dissolvable configuration, no drugs are coated on the needle surface so no drug will peel off and stay outside the skin during the insertion process. However, it is reported that the penetration depth is normally much less than the full length of the needles due to the elastic and stretchy nature of the skin. For example, 500um microneedles will only have a penetration depth of 250um - 300um. For an array of 1000 microneedles, each microneedle will have different penetration depth and therefore different dose delivery, which eventually leads to unquantifiable dose. US patent 8,167,852B2 awarded to Cosmed Pharmaceutical Co., Ltd. Reported such configuration, in which the microneedles are made with mixture of dissolvable material hyaluronic acid and the drug collagens.
Another critical issue in dissolvable microneedles is the dissolving time. In Cosmed's patent '852, the dissolvable material used is hyaluronic acid (HA), which has molecular weight of 5,000— 20,000,000 Da. Long duration is required for the HA to dissolve in the skin after penetration.
The typical dissolving duration required is half an hour to an hour, which may be too long for most medical applications such as hypersensitivity diagnosis and treatment, vaccination, and allergic skin testing. Hence, rapid delivery of active pharmaceutical ingredients such as antigens, hormones, vaccines and other drugs by microneedles are highly desirable.
There is a need for painless, cold-chain free, rapidly dissolving and user friendly drug delivery system which ensure complete delivery of the API for the purposes of vaccination, screening of tuberculosis, diagnosis and treatment of hypersensitivity, allergic skin testing, etc. The present invention seeks to provide a solution to this need.
SUMMARY OF THE INVENTION
The present invention involves a drug patch of rapidly dissolvable microneedles comprising needle tips that are impregnated with drugs and the use" of the rapidly dissolvable microneedles for delivering drugs transdermally. In the preferred embodiment, the rapidly dissolvable microneedle patch 10 comprises a plurality of microneedles or tiny spikes 20 which are disposed on a back layer 30. The microneedles 20 have tapered geometry and have two parts on each microneedle 20, namely the drug tip 22 and the needle body 24. The drug tip 22, which occupies only a fraction of the volume of the apex of the microneedle, contains active pharmaceutical ingredients which are impregnated into the microneedle by centrifuging. In practice, only a portion of the microneedle 20 will be inserted into the skin. The penetration line 26 is an imaginary line dividing the inserted portion 32 of the microneedle 20 (inserted into the skin) and the non-inserted portion 34 of the microneedle 20 when the microneedle 20 is inserted into the skin. The inserted portion 32 extends from the apex 28 of the microneedle to the penetration line 26, and the non-inserted portion 34 extends from the penetration line 26 to the base 29 of the microneedle. In this way, the drug tip 22 which stays within the inserted portion 32 of the microneedle 20 is guaranteed to be fully delivered to the skin.
The present invention also includes a fabrication method for making rapidly dissolvable microneedles with tips that are impregnated with drugs. In yet another preferred embodiment, a master mould 100 of metal microneedle array is fabricated. Microneedle templates 200 are duplicated from the master mould 100 via conventional techniques such as injection moulding of liquid silicone rubber, room temperature vulcanizing (RTV) silicone casting, and plastic injection moulding. Next, drug in liquid form is dispensed into the cavities 220 on microneedle templates 200 and the templates are spun using a centrifuge until the excipients are vaporized. The
spinning will ensure that the drug fills up the cavity completely and forms drug tips 240. Next, the dissolvable material such as micro-hyaluronic acid at various concentrations is dispensed on the templates 200 and spun briefly using a centrifuge to form the needle body 260 and the back layer 280.
Lastly, the present invention covers a method for applying a rapidly dissolvable microneedle patch 540 and delivering full dose to the skin 560 reliably. The method involves tensioning the skin by a transparent compression ring 520 and rapidly inserting the rapidly dissolvable microneedles 580 into the skin 560 and subsequently pressing the patch 540 against the skin 560 for the dissolving duration. The active pharmaceutical ingredient which is always impregnated within the penetration line is inserted fully into the skin for ensuring complete dose delivery.
BRIEF DESCRIPTIONS OF THE DRAWINGS
Fig. 1 is the perspective view of the rapidly dissolvable microneedle patch
Fig. 2 is the close-up view of the rapidly dissolvable microneedle showing the drug- impregnated tip and the needle body
Fig. 3 is the preferred packaging configuration of the rapidly dissolvable microneedle patch
Fig. 4 is a schematic diagram showing the process flow for making rapidly dissolvable micronneedles with drug-impregnated tips
Fig. 5 (a)— (d) are schematic diagrams showing the penetration steps of the rapidly dissolvable microneedles which leads to complete dose delivery
Fig. 6 (a) and (b) are photographs of the rapidly dissolvable microneedles before and after skin penetration, showing complete dose delivery
DETAILED DESCRIPTION OF THE INVENTION
Advantages and Disadvantages of Dissolvable Microneedles
Dissolvable microneedles are developed recently to address several issues of the dry-coated solid microneedles. Apart from the fact that the coated drug can be peeled off easily from the needle surface during the insertion process, drug loading of the solid microneedles (i.e. the amount of
the drug coat-able on the needle surface) remains a great drawback. There are attempts where excessive drugs are coated on the needle surface until the drug forms a lump on the needle surface. The lump forms an irregular surface that hinders the insertion of the microneedles into the skin and normally will fall off the surface before penetrating into the skin. On the other hand, drugs are impregnated into dissolvable microneedles so there is no alien, irregular lump to adhere on the needle surface which is prone to falling off the surface before penetrating into the skin. As the drug is within the needle body, the amount of drug that can be loaded into a needle increases 10 to 100 folds.
However, there are some issues that current dissolvable microneedles still need to address. For instance, the characteristics of the dissolvable material have to be such that it is dissolvable upon contact with skin but it should be moist and heat resistant for transportation and storage. The material has to also provide sufficient hardness for effective penetration. Currently the materials used for making dissolvable microneedles are either too soft (e.g. sucrose, poly-lactic acid (PLA) or Poly- (Ethylene Glycol) Diacrylate (PEGDA), too susceptible to moist (e.g. PVP), or take too long to dissolve (e.g. hyaluronic acid by Cosmed which is 5,000— 20,000,00 kDa in size). Lasdy, it is now known that the actual penetration is only a portion of the full height of the microneedles. Most of the dissolvable microneedles lack the ability to quantify the final dose because the microneedles are designed with the assumption that full insertion of the microneedles is achieved. As a result drugs are impregnated in the whole body of the needle, not the tips, leading to variable final dose.
Rapidly Dissolvable Microneedles with Drug-Impregnated Tips
The present invention involves a patch of rapidly dissolvable microneedles comprising tips that are impregnated with drugs and the use of the rapidly dissolvable microneedles for delivering drugs transdermally. Figure 1 shows the preferred embodiment of a rapidly dissolvable microneedle patch that contains tips impregnated with drugs. In the preferred embodiment, the rapidly dissolvable microneedle patch 10 comprises a plurality of microneedles or tiny spikes (or microneedles) 20 which are disposed on a back layer 30.
The microneedles 20 have tapered geometry such as but not limited to pyramidal or conical shape and have two parts on each microneedle 20, namely the drug tip 22 and the needle body 24. The drug tip 22, which occupies only a fraction of the volume of the apex of the microneedle, contains active pharmaceutical ingredients which are impregnated into the microneedle by
centrifuging. The drug tip 22 occupies only a fraction of the volume of a microneedle. The drug tips 22 are formed by vaporizing a liquid drug using a centrifuge to dehydrate the drug to reduce the volume. The liquid drug can be vaccines, hormones, peptides and other biologies. The drug tips 22 normally span 50um to lOOum from the tip and do not occupy more than 5% of the total volume of the microneedle. The needle body 24 and the back layer 30 are made from dissolvable material such as chitosan, micro-hyaluronic acid, and hydrogels. In a typical configuration, the drug tip 22 may have a length of OOum from the tip and the needle body 24 may have 400um - 500um length from the drug tips 22. The drug tips 22 have a tip size of 5um to lOum and the needle body 24 has a square base of 150um to 200um. The back layer 30 has a thickness of 0.5mm to 2mm. The needle body 24 and the back layer 30 can be made with the same material or they can be made with different materials.
In practice, only a portion of the microneedle 20 will be inserted into the skin due to the skin's elasticity and deformability. Therefore, a microneedle when inserted into the skin has two portions, one which is inserted into the skin and dissolves and another one which stays out of the skin and does not dissolve. It is very critical to identify penetration depth so that the drugs can be impregnated only within the inserted portion. So, a penetration line 26 is an imaginary line dividing the inserted portion 32 of the microneedle 20 (inserted into the skin) and the non- inserted portion 34 of the microneedle 20 when the microneedle 20 is inserted into the skin. The inserted portion 32 extends from the apex 28 of the microneedle to the penetration line 26, and the non-inserted portion 34 extends from the penetration line 26 to the base 29 of the microneedle. In this way, the drug tip 22 which stays within the inserted portion 32 of the microneedle 20 is guaranteed to be fully delivered to the skin.
Figure 2 shows a close-up view of one rapidly dissolvable microneedle 40, comprising the drug tip 22, needle body 24, an imaginary penetration line 26 and the back layer 30. The drug tip 22 is made of drug which spans from the apex of the microneedle. The penetration line 26 is an imaginary line separating the penetrated portion (or the dissolved portion) 32 of the rapidly dissolvable microneedle 40 (inserted into the skin 34) and the un-penetrated portion (or the remaining portion) 36 of the rapidly dissolvable microneedle 40 when it is inserted into the skin 34. The drug tip 22 is always kept within the penetration line 26 so that it is always fully inserted into the skin 34.
The depth or distance of the penetration line 26 from the apex is determined by various factors, including the length of the microneedle, the insertion, force and speed, the geometry and sharpness of the microneedles, the mechanical strength of the material, the hygroscopic and
most importantly, the wear time or dissolving duration of the rapidly dissolvable microneedle. For example, with roughly lm/s insertion speed and 0.1 N insertion force, a 600um tall rapidly dissolvable microneedle made with uHA may dissolve 200um for a wear time of 10 seconds. In this case, the penetration line 26 is 200um deep from the apex and the drug tip 22 can be as long as 200um from the apex.
For example, a drug of hepatitis B vaccine which has a volume of 0.3ml and which contains lOug of antigens can be impregnated into the rapidly dissolvable microneedle 40 and form the drug tip 22, and micro-hyaluronic acid (uELA) with molecular weight between 3— 10 kDa can be used to form the needle body 24 and the back layer 30. It is found that uHA provides the structural strength for the rapidly dissolvable microneedles 40 to penetrate the skin, remains stable for wide range of temperature and humidity, and becomes extremely dissolving when in contact with inner skin (penetrated skin).
Figure 3 shows a preferred packaging configuration 50 comprising a transparent casing 60, and a sealing film 70. The transparent casing further comprises a sealing surface 52 onto which the sealing film 70 will be affixed, a first compartment 54 immediately following the sealing surface 52 for receiving the back layer 30 of the microneedle patch, and a second compartment 56 which is smaller and immediately underneath the first compartment 54 for receiving the microneedles 20, and a flat surface 58 between the two compartments acting as a seat for the back layer 30. The transparent casing 60 may be thermo-formed, injection moulded or machined. The sealing film 70 may be made of insulating material such as polymer or aluminum which may be affixed to the sealing surface 52 of the transparent casing 60 via pressure- or heat-sensitive adhesive.
In summary, the advantages for a rapidly dissolvable microneedle patch are namely 1) it is painless; 2) it dissolves instantly so it is suitable for replacing parenteral (injection) drug adrninistration; 3) it deliver drugs precisely into the epidermal layer (200um - 300um below stratum corneum), this is ideal for point-of-care diagnostic skin tests such as tuberculosis, hypersensitivity and allergy which currently rely on Mantoux technique (extremely painful), which injects 0.1ml of liquid drug intradermally; 4) the active pharmaceutical ingredients can be preserved by the sugars so cold chain is not required for the transportation and storage of the microneedle patches.
As such, the potential uses of the present invention are vaccination, diagnosis and treatment of hypersensitivity and allergy, and tuberculosis point-of-care diagnostic tests.
Fabrication of Rapidly Dissolvable Microneedles with Drug-Impregnated Tips
Now the process for fabricating the rapidly dissolvable microneedles which comprise drug- impregnated tips will be described. Figure 4 shows a schematic diagram of the flow of the fabrication process. First, a microneedle master mould 100 comprising the desired microneedle geometry and array size is fabricated. The fabrication technique can range from grinding, to precision wire cutting, to micro fabrication processes, which are well known in the art. Next, a moulding material is cast over the master mould 100 to form a template 200 which comprises the negative shape of the master mould 100. A suitable moulding material is typically silicone with various hardness indices, and the choice of material is not limited to silicone. A person skilled in the art will have the knowledge in determining a suitable material to form the template. After a de-moulding process, which separates the template 200 from the master mould 100, precise amount of active pharmaceutical ingredient (API) 300, which includes but not limited to vaccines, hormones, antigens, antibodies, peptides and other biologies, can be spotted onto the template cavities 220 and the template 200 is subjected to a centrifugal process, normally but not limited to 3,000— 5,000 rpm spinning for 30— 300 seconds. The centrifugal process ensures that the template cavities 220 are completely filled up by the active pharmaceutical ingredient (API) 300 and that the excipient of the active pharmaceutical ingredient (API) 300.
Most of the time, to enhance the hardness for effective penetration, the active pharmaceutical ingredient (API) 300 may be pre-mixed with a strengthening substance such as polyethylene glycol diacrylate (PEGDA), polyvinylpyrrolidone (PVP), micro-hyaluronic acid (μΗΑ), which has a molecular size of 3— 5 kDa, and so on. In this case, the centrifugal process ensures complete filling of the template cavities 220 and therefore the formation of the drug-impregnated tips 240.
Alternatively, the mixing can be achieved by first spotting the strengthening substance into the template cavities 220 and subjecting the template 200 to a centrifugal process, and then immediately spotting the active pharmaceutical ingredient (API) 300 into the template cavities 220 and subjecting the template 200 to a second centrifuging process, which mixes the strengthening substance and the active pharmaceutical ingredient (API) 300. Subsequently, the same strengthening substance or a new substance can be added onto the template 200 to form the rest of the microneedle body 260 and the back layer 280 of the microneedle patch. The template 200 is subjected to another centrifugal process to ensure complete fusion of the drug- impregnated tips 240 with the microneedle body 260 and the back layer 280. Lastly, the rapidly dissolvable microneedle patch comprising drug-impregnated tips is de-moulded from the template 200 and packed individually.
The inventor discovered that micro-hyaluronic acid (μΗΑ) with molecular size of 3,000 - 5,000 Da has several unique characteristics that make it the ideal candidate fo the strengthening substance: (1) it provides sufficient mechanical strength for effective skin penetration; (2) it dissolves instantly when made in contact with the skin; (3) it exhibits excellent moist and temperature resistance which are vital for transportation and storage. It is obvious that other rapidly dissolvable materials which provide sufficient mechanical strength can also be used to make rapidly dissolvable microneedles. Other potential materials are chitosan, PVP, PEDGA, and other smart polymers.
Application Method of Rapidly Dissolvable Microneedles to Ensure Complete Dose Delivery
Now the technique to ensure complete dose delivery will be described. Complete dose delivery is vital for drug delivery effectiveness. Current microneedle patches coat the drug load on the surface of the microneedles and a portion of the drug load will inevitably stay outside of the skin during the penetration process. Incomplete delivery is the largest hindrance to having consistent clinical trial results. Since our drug load is impregnated into the tips of our rapidly dissolvable microneedles, we have found a solution to overcome this critical issue.
It is discovered by the inventor that the insertion of microneedles is most effective when the skin is tensioned and the microneedles are inserted at a speed of lm/s— 6m/s.- Mild compression force of roughly 0.1N - 1.0N is also required to hold the inserted microneedles in the skin, which otherwise will be pushed out of the skin by the body. Hence, the application procedure is normally assisted by a spring-operated actuator to perform the skin tensioning, high-speed insertion and post-insertion holding steps. Figures 5(a) - 5(d) show how a rapidly dissolvable ' microneedle with drug-impregnated tip penetrates the skin and delivers the complete dose into the skin.
In Fig. 5(a), a microneedle applicator 500 with a transparent skin tensioning ring 520, which is loaded with a rapidly dissolvable microneedle patch 540, is compressed onto a skin site 560. The preferred skin sites are but not limited to outer upper arms, inner and outer lower arms, and stomachs. The compression force provided through the transparent skin tensioning ring 520 is between 0.1N - 1.0N such that the skin site 560 is sufficiently tensioned (stretched) and fixed. The transparent skin tensioning ring 520 is held with the compression force onto the skin throughout the application procedure.
8
Next, as shown in Fig. 5(b), the rapidly dissolvable microneedle patch 540 is inserted into the skin at the predetermined speed, e.g. lm/s - 6m.s. There is a need to have some distance, e.g. 5mm - 15mm, between the initial position of the dissolvable microneedle patch 540 and the ski site 560 so that the patch can attain the predetermined speed at the point of penetrating the skin. The insertion speed is normally provided by a spring (not shown). The insertion of microneedles 540 is not full length; only 200um - 300um of the microneedles will be inserted into the skin normally. When inserted, the skin site 560 will form a penetration line 600 that separates the inserted portion of the microneedles 620 and non-inserted portion of the microneedles 640. The penetration line 600 coincides with the penetration depth, which is 200um— 300um from the apex 660 of the microneedles 580. To ensure complete delivery of the dose, active pharmaceutical ingredients are impregnated between the apex 660 of the microneedles 580 and the penetration line 600.
Once the microneedles 580 penetrate the stratum corneum (the outer layer of the skin, not shown), the inserted portion of the microneedles 620 starts to dissolve instantly. It is very important to hold the inserted portion of the microneedles 620 in the skin site 560 so that the dissolving can be completed, normally within 10 seconds to one minute. Therefore, there is a holding force of 0.1 N - 1.0N to hold the inserted portion of the microneedles 620 in the skin site 560 for the dissolving duration. The holding force is normally provided by the same spring (not shown) that provides the insertion speed-. The holding and the dissolving of the inserted portion of microneedles 620 and is shown in Fig. 5(c).
Lastly, as shown in Fig. 5(d), the applicator 500 as well as the non-inserted portion of the microneedles 640 are removed from the skin site 560 and the inserted or dissolved portion of the microneedles 620 remain in the skin site 560.
The effectiveness of the rapidly dissolvable microneedles with drug-impregnated tips can be shown in Figs. 6(a) and 6(b). ,. Figure 6(a) shows a rapidly dissolvable microneedle patch comprising tips impregnated with blue dye. The blue dye was impregnated within the apex of the microneedles and the penetration line, or more particularly, within lOOum from the apex. After insertion of the microneedles according to the procedure shown in Figs. 5(a) - 5(d), all the blue- dyed portion of the microneedles dissolved in the skin, leaving only the non-inserted portion of the microneedles, which is shown in Fig. 6(b).
Claims
1. A rapidly dissolvable microneedle made from a rapidly dissolving material for medical use, comprising
a. A needle body which is made of the rapidly dissolving material;
b. A drug tip which is the apex of the microneedle where active pharmaceutical ingredient is impregnated;
c. An imaginary penetration line dividing the microneedle into a first and a second portion such that:
when the microneedle is applied to the skin, the first portion, which extends from the apex to an imaginary penetration line, is fully inserted into a skin; and that the second portion of the microneedle, which extends from the imaginary penetration line to the base of the microneedle, stays outside of the skin; wherein the drug tip is disposed between the apex of the microneedle and the penetration line.
2. A rapidly dissolvable microneedle in claim 1, wherein the rapidly dissolvable microneedle is inserted into a skin site with high speed.
3. A rapidly dissolvable microneedle in claim 1, wherein insertion speed of the rapidly dissolvable microneedles is between lm/ s— 6m/ s.
4. A rapidly dissolvable microneedle in claim 1, wherein the rapidly dissolvable material is micro-hyaluronic acid.
5. A rapidly dissolvable microneedle in claim 1, wherein the micro-hyaluronic acid has molecular weight of 3,000 - 5,000 Da.
6. A rapidly dissolvable microneedle in claim 1, wherein the imaginary penetration line is 200um from the apex of the microneedle.
7. A rapidly dissolvable microneedle in claim 1, wherein the imaginary penetration line is 300um from the apex of the microneedle.
8. A rapidly dissolvable microneedle in claim 1, wherein the active pharmaceutical ingredient comprises vaccines for vaccination purpose
9. A rapidly dissolvable microneedle in claim 1, wherein the active pharmaceutical ingredient comprises hormones for therapeutic purpose.
10. A rapidly dissolvable microneedle in claim 1, wherein the active pharmaceutical ingredient comprises antigens and antibodies for diagnosis and treatment of hypersensitivity purpose.
11. A method of fabricating rapidly dissolvable microneedles with drug-impregnated tips, comprising:
a. Providing a master mould of microneedles;
b. Fabrication of a secondary mould with negative structure of the master mould; c. Addition of active pharmaceutical ingredient onto the secondary mould and subjecting me secondary mould to a first centrifugal force;
d. Addition of dissolving material onto the secondary mould and subjecting the secondary mould to a second centrifugal force; and
e. Retrieval of the microneedles by de-moulding it from the secondary mould.
12. A method of fabricating rapidly dissolvable microneedles with drug-impregnated tips in claim 11 , wherein the first centrifugal force is achieved by 3,000 - 5,000 rpm rotation.
13. A method of fabricating rapidly dissolvable microneedles with drug-impregnated tips in claim 11 , wherein the second centrifugal force is achieved by 3,000 - 5,000 rpm rotation.
14. A method of fabricating rapidly dissolvable microneedles with drug-impregnated tips in claim 11, wherein the dissolving material is micro-hyaluronic acid.
15. A method of fabricating rapidly dissolvable microneedles with drug-impregnated tips in claim 11, wherein the micro-hyaluronic acid has molecular weight of 3,000— 5,000 Da.
16. A method of applying the rapidly dissolvable microneedles, comprising
a. Tensioning and fixing a skin site by compressing the skin site by a ring with a compression force throughout the procedure;
b. Actuating the microneedles normally and inserting the microneedles into the skin at high speed;
c. Holding the microneedles in the skin so that they will not dislodge for effective dissolving within the holding duration; and
d. Removing the holding force, the compression force and the microneedles from the skin site after the application is complete.
17. A method of applying the rapidly dissolvable microneedles in claim 16, wherein the compression force is 0.1N - 1. ON.
18. A method of applying the rapidly dissolvable microneedles in claim 16, wherein the insertion speed of the microneedle is lm/ s— 6m/ s.
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CN114558241A (en) * | 2021-12-31 | 2022-05-31 | 北京化工大学 | Drug administration type endoscope device based on polymer soluble microneedle |
CN114558241B (en) * | 2021-12-31 | 2024-01-12 | 北京化工大学 | Drug delivery type endoscope device based on polymer soluble microneedle |
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