CN115212432B

CN115212432B - Medicine carrying saccule

Info

Publication number: CN115212432B
Application number: CN202210756402.9A
Authority: CN
Inventors: 汪令生; 王秀伟; 董志会; 罗玉萍; 李文松
Original assignee: Kossel Medtech Suzhou Co ltd
Current assignee: Kossel Medtech Suzhou Co ltd
Priority date: 2022-06-30
Filing date: 2022-06-30
Publication date: 2024-01-30
Anticipated expiration: 2042-06-30
Also published as: CN115212432A

Abstract

The embodiment of the specification discloses a medicine carrying balloon, which comprises a balloon and a medicine coating arranged on the balloon, wherein the medicine coating comprises a medicine and an additive, and the additive comprises a water-soluble polymer auxiliary agent with low crosslinking degree, a weakly alkaline first additive and a fat-soluble second additive.

Description

Medicine carrying saccule

Technical Field

The specification relates to the field of medical equipment, and in particular relates to a medicine carrying balloon.

Background

Urethral stricture is one of the most common urinary surgical diseases in clinic, and is a major problem in male patients. In some applications, the treatment may be performed by releasing the drug into the focal site through a drug-loaded balloon.

However, due to poor drug passage through the urethral wall and the special physiological environment of the urethra (e.g., normal urine appears weakly acidic, wall adhesions, rough urethral mucosa, etc.), the drug transfer rate of the drug-carrying balloon is often less than ideal. Therefore, in order to ensure that the drug can be stably coated on the drug-carrying balloon and can not be washed by body fluid and absorbed by the urethral wall, it is desirable to provide the drug-carrying balloon applied to urethral stricture for improving the long-term effect after urethral stricture dilatation or incision treatment.

Disclosure of Invention

The embodiment of the specification provides a medicine carrying balloon, which comprises a balloon and a medicine coating arranged on the balloon, wherein the medicine coating comprises a medicine and an additive, and the additive comprises a water-soluble polymer auxiliary agent with low crosslinking degree, a weakly alkaline first additive and a fat-soluble second additive.

In some embodiments, the water-soluble low-crosslinking polymeric auxiliary comprises at least one of a third additive, a fourth additive, and a fifth additive; wherein the third additive comprises an alkyl fatty group or a group of bile fibers; the fourth additive comprises polyethylene glycol or polyglycerol; the fifth additive includes at least one of salicylic acid, allantoin, and lactic acid.

In some embodiments, the first weakly basic additive comprises any one or a combination of urea, organic amine, organic base, magnesium stearate, calcium stearate, and the second fat-soluble additive comprises one or a combination of PEG stearate, phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, amine derivatives of phosphatidylcholine.

In some embodiments, the water-soluble low-crosslinking polymeric auxiliary agent comprises 0.1% -15% by weight of the drug coating, the weakly basic first additive comprises 0.1% -45% by weight of the drug coating, the fat-soluble second additive comprises 0.1% -55% by weight of the drug coating, and the drug comprises 35% -75% by weight of the drug coating.

In some embodiments, a hydrophilic protective layer is also disposed on the balloon, the hydrophilic protective layer being wrapped over the drug coating.

In some embodiments, the hydrophilic protective layer comprises any one or combination of crystalline sugar, glycan, and polyvinylpyrrolidone.

In some embodiments, the additive further comprises a sixth additive that imparts a positive electrokinetic potential to the drug coating.

In some embodiments, the sixth additive comprises a glycerophospholipid ionomer.

In some embodiments, the balloon comprises a plurality of balloon petals in a collapsed state, at least two adjacent balloon petals of the plurality of balloon petals being rolled in opposite directions in a collapsed state to form a cavity between adjacent balloon petals.

In some embodiments, at least a portion of the drug coating is disposed in the cavity.

Additional features will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following and the accompanying drawings, or may be learned by the production or operation of the examples. The features of the present specification can be implemented and obtained by practicing or using the various aspects of the methods, tools, and combinations set forth in the detailed examples below.

Drawings

The present specification embodiments will be further described by way of exemplary embodiments, which will be described in detail with reference to the accompanying drawings. The embodiments are not limiting, in which like numerals represent like structures, wherein:

fig. 1 is a schematic structural view of a drug-loaded balloon provided in some embodiments of the present disclosure.

Fig. 2 is a schematic structural view of a hydrophilic protective layer of a drug-loaded balloon according to some embodiments of the present disclosure.

Fig. 3 is a schematic view of a balloon structure of a drug-loaded balloon according to some embodiments of the present disclosure.

Fig. 4 is a schematic view of a balloon structure of a drug-loaded balloon according to other embodiments of the present disclosure.

Detailed Description

In order to more clearly illustrate the technical solutions of the embodiments of the present specification, the drawings used in the description of the embodiments will be briefly described below. It is apparent that the drawings in the following description are only some examples or embodiments of the present specification, and it is possible for those of ordinary skill in the art to apply the present specification to other similar situations according to the drawings without inventive effort. It should be understood that these exemplary embodiments are presented merely to enable one skilled in the relevant art to better understand and practice the present description, and are not intended to limit the scope of the present description in any way. Unless otherwise apparent from the context of the language or otherwise specified, like reference numerals in the figures refer to like structures or operations.

As used in this specification and the claims, the terms "a," "an," "the," and/or "the" are not specific to a singular, but may include a plurality, unless the context clearly dictates otherwise. In general, the terms "comprises" and "comprising" merely indicate that the steps and elements are explicitly identified, and they do not constitute an exclusive list, as other steps or elements may be included in a method or apparatus. The term "one embodiment" means "at least one embodiment"; the term "another embodiment" means "at least one additional embodiment".

In the description of the present specification, it should be understood that the terms "distal," "proximal," "inner," "outer," "distal," "proximal," "one end," and the like indicate orientations or positional relationships based on the orientation or positional relationships shown in the drawings, merely to facilitate description of the present specification and simplify the description, and do not indicate or imply that the device or element being referred to must have a particular orientation, be configured and operated in a particular orientation, and thus should not be construed as limiting the present specification.

In the present specification, unless explicitly stated and limited otherwise, terms such as "connected," "disposed," and the like are to be construed broadly, and for example, "connected" may be a fixed connection, a removable connection, or an integral body; can be directly connected or indirectly connected through an intermediate medium; may be a communication between two elements or may represent an interaction between two elements. Unless otherwise specifically defined, it will be understood by those of ordinary skill in the art that the specific meaning of the terms in this specification is to be understood as appropriate.

Urethral stricture is a disease in which the urethral mucosa is damaged by causes such as congenital, iatrogenic, and exogenous causes, and scar formation occurs in the urethral mucosa or the urethral cavernous body surrounding the urethral mucosa during repair of the damage, thereby narrowing the urethra. At present, the balloon dilation has been applied to the improvement and treatment of urethral stricture, has the advantages of no need of step-by-step dilation, capability of adjusting the dilation pressure and balloon specification parameters according to the stricture degree, softer dilation process and the like, and can solve the problems of longer operation time and poor body feeling of patients.

Drug-loaded balloons are novel interventional techniques developed on the basis of balloon dilation by coating the surface of the balloon with therapeutic agents having specific therapeutic effects, and when the balloon is delivered to a focal site, it is expanded under pressure to contact the urethral wall, releasing pressure rapidly by tearing the inner membrane of the urethral wall, and simultaneously transferring the drug-loaded to the urethral wall.

However, due to poor drug passage properties of the urethral wall and special urethral physiological environment (e.g., normal urine exhibits weak acidity (urine pH value is 4.6-8.0, average 6.0), wall adhesion, urethral mucosa roughness, etc.), the drug transfer rate of the current drug-carrying balloon is generally not ideal.

In order to solve the above problems, embodiments of the present application provide a drug-loaded balloon, which reduces the loss of the drug coating during the balloon delivery process by adding an additive to the drug coating, thereby improving the drug transfer rate.

The drug-loaded balloon provided in the embodiments of the present specification will be described in detail with reference to the accompanying drawings.

Referring to fig. 1, drug-loaded balloon 100 may include balloon 110, catheter hub 120, catheter shaft 130, and visualization ring 140. Wherein, the catheter shaft 130 may include an inner tube 131 and an outer tube 132, the outer tube 132 is sleeved outside the inner tube 131, one ends of the inner tube 131 and the outer tube 132 are connected with the catheter holder 120, and the balloon 110 is sleeved outside one end of the inner tube 131 far away from the catheter holder 120. In some embodiments, the gap between the inner tube 131 and the outer tube 132 may be in communication with the interior space of the balloon 110, constituting a control channel for controlling the inflation or deflation of the balloon 110. Specifically, i.e., in some embodiments, gas or liquid may be injected/extracted into the interior of balloon 110 through the gap between inner tube 131 and outer tube 132 to control inflation/deflation of balloon 110.

With continued reference to fig. 1, a visualization ring 140 may be disposed on the inner tube 131 inside the balloon 110, and the visualization ring 140 may be imaged under x-ray or ultrasound detection to mark the approximate location of the balloon 110, thereby facilitating an operator (e.g., a physician) to observe the location of the balloon 110. In some embodiments, drug-loaded balloon 100 may include two or more development rings 140, which two or more development rings 140 may be disposed inside balloon 110 and along inner tube 131. For example, in some embodiments, drug-loaded balloon 100 may include two visualization rings 140, which two visualization rings 140 may be disposed on inner tube 131 and aligned with both ends of balloon 110.

In some embodiments, the outer surface of balloon 110 may include a drug coating (not shown) having a specific therapeutic effect, and when balloon 110 is delivered to a focal location (e.g., the urethral wall), the outer surface of balloon 110 may be forced into contact with the focal location while the drug-loaded on the outer surface of balloon 110 is transferred to the focal location.

In some embodiments, additives with specific functions may be added to the drug coating in order to increase the drug transfer rate at the urethral wall, reduce drug loss, enhance tissue absorption, and increase the therapeutic effect of the drug-loaded balloon. The additive may include at least one of a water-soluble polymer auxiliary agent with low crosslinking degree, a weakly basic first additive, and a fat-soluble second additive. For example, in some embodiments, a weakly basic first additive may be added to the drug coating; in some embodiments, a second, fat-soluble additive may be added to the drug coating; in some embodiments, a water-soluble, low-crosslinking polymeric adjuvant may be added to the drug coating. For another example, in some embodiments, the aforementioned weakly basic first additive, the fat-soluble second additive, and the water-soluble low-crosslinking polymeric auxiliary agent may be added simultaneously to the drug coating. It should be noted that, in the present specification, the term "weakly alkaline" may mean that the pH value is less than a certain threshold value, for example, pH.ltoreq.9; the term "degree of crosslinking", also known as crosslink density, refers to the fraction of structural units that can be crosslinked relative to the total structural units, and "low degree of crosslinking" may refer to less than 10 structural units out of 50 to 100 structural units being crosslinked. In some embodiments, "low degree of crosslinking" may refer to a ratio of structural units that are crosslinked to total structural units of less than 10%. In some examples, the solvent resistance is good when the degree of crosslinking is large, but the swelling degree is small, and the swelling degree is large when the degree of crosslinking is small, but the solvent resistance is poor, and based on this, in the examples of the present specification, a substance having a degree of crosslinking of 5% to 10% may be selected as the polymer auxiliary agent having a low degree of crosslinking.

Since the ph has a greater effect on the dissociation degree of the drug (i.e., the ratio of the number of dissociated drug molecules to the number of original drug molecules when the drug reaches dissociation equilibrium), which is an important factor affecting the permeation of the drug through the cell membrane, in order to reduce its effect on the dissociation of the weakly basic drug in the physiological environment of the urinary tract, in some embodiments, a weakly basic first additive may be added to the drug coating. By adding the first additive, the pH value of body fluid stabilizing the urethral wall can be changed/buffered, so that the stability of the weakly alkaline medicament in the urethra is improved, the dissociation degree of the weakly alkaline medicament in the urethra is reduced, the condition that the medicament is difficult to permeate cell membranes due to overlarge dissociation degree is avoided, and the medicament effect can be better exerted.

In some embodiments, the weakly basic first additive may include any one of urea, an organic amine (e.g., polyacrylamide), an organic base, magnesium stearate, calcium stearate, or a combination thereof. When the first alkalescent additive adopts urea, organic amine or organic alkali, not only the stability of the medicine can be improved, but also the medicine penetrating amount can be effectively improved. When the first alkalescent additive is magnesium stearate or calcium stearate, the buffer salt can be used for adjusting the pH value of the urethra, so that the dissociation effect of the urethra physiological environment on the medicine is further weakened, and the stability of the medicine in the urethra is further improved.

It should be noted that the first additive shown above is only exemplary, and in some other embodiments, the first additive may be replaced with other substances having similar or identical properties. In addition, it should be noted that in some special cases, the physiological environment of the urethra may be slightly alkaline, and in this case, if the drug is slightly acidic, a slightly acidic first additive may be added to the drug coating to improve the stability of the drug in the urethra and reduce its dissociation degree, based on the same principle.

In some embodiments, in order to allow the drug component to exist in molecular form, which allows for the molecular drug to diffuse across the membrane, but not the ionic drug component, a second, liposoluble additive may be added to the drug coating to facilitate penetration into the cell lipid membrane and to disturb the surface phospholipid bilayer, to accelerate drug penetration into tissue cells to enhance tissue absorption, when the drug is transverted to the urethral wall. Illustratively, in some embodiments, the fat-soluble second additive may include one of PEG stearate, phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, amine derivatives of phosphatidylcholine, or any combination thereof. In some embodiments, the second additive can be effectively inserted between drug molecules at intervals, so that a porous coating with a high contact surface is formed between the lipophilic drug molecules and the urethral wall, thereby increasing the specific surface area of the drug and improving the drug transfer rate and the utilization rate.

Further, in some embodiments, in view of the specific physiological function of the urethra, when the balloon dilation is used for dilation, the dilation time may take from 5 minutes to 10 minutes, or even longer, and if the drug is released at too fast a rate, it may be eluted during delivery and be eroded. Therefore, in order to avoid the drug coating from dissolving out during the delivery process or before reaching the focus position, causing a great amount of delivery loss of the drug, a water-soluble polymer auxiliary agent with low crosslinking degree can be added into the drug coating, and the water-soluble polymer auxiliary agent with low crosslinking degree can be used for controlling the dissolution and release time of the drug and slowing down the dissolution and release of the drug on the balloon 110, so that the dissolution time of the drug is matched with the expansion time of the drug-carrying balloon 100. In other words, the dissolution release time of the drug coating can be controlled to be 5min-10min, or even longer, by adding the water-soluble polymer auxiliary agent with low crosslinking degree into the drug coating.

In some embodiments, the water-soluble low crosslinkingThe polymeric auxiliary may include at least one of a third additive, a fourth additive, and a fifth additive, wherein the third additive may include an alkyl fatty group or a bile fiber group, and the molecular weight thereof may be between 350 and 750; the fourth additive may include polyethylene glycol (- (CH) ₂ CH ₂ O) -) or polyglycerol (- (CH) ₂ -CHOH-CH ₂ O) -) units; the fifth additive may include at least one of salicylic acid, allantoin, and lactic acid. In some embodiments, the fourth additive polymer may include polar groups such as hydroxyl groups and amino groups, where the polar groups can form hydrogen bonds with drug molecules to generate greater viscosity, so as to play a role in slowing down drug dissolution and reducing drug loss. However, on the other hand, the addition of the polymer with low crosslinking degree increases the overall thickness of the surface coating of the balloon 110 to a certain extent, prolongs the path of the drug transferred from the balloon to the urethral wall, and indirectly reduces the drug transfer rate. Based on this, in some embodiments of the present description, the weight ratio of the third additive and/or the fourth additive may be controlled to be between 0.1% and 5%.

Further, in some embodiments, the phenomenon of roughness of the urethral mucosa is evident in view of the specific physiological functions of the urethra, particularly the increase of the wall adhesions of the urethra in the case of urethral strictures. Thus, when the balloon 110 is expanded, due to the limitation of the compliance of the balloon, the balloon body may not be completely and seamlessly attached to the surface of the urethral wall with rough surface or even adhesion, and some contact gaps may exist, so that the contact is impossible and the drug transfer is affected. In some embodiments of the present disclosure, the low crosslinking polymeric auxiliary agent may include a fourth additive, wherein the fourth additive may include polyethylene glycol (- (CH) ₂ CH ₂ O) -) or polyglycerol (- (CH) ₂ -CHOH-CH ₂ O) -) units, in some embodiments, the fourth additive polymer may contain polar groups such as hydroxyl groups, amino groups, etc., and in aqueous solution, the intermolecular hydrogen bond hydration is sufficiently extended to allow the polymer gel to swell to some extent, have some flexibility and ductility, and may wrap around and conform to the rough urethral wall surface, thereby contributing to the overall balloonAnd the drug loaded on the body is effectively transferred. In some embodiments, the fourth additive may be at least one of chitosan, gelatin, PVA0588 (polyvinyl alcohol with an average degree of polymerization of 500-600, an alcoholysis degree of 88%), PEGDA (Polyethylene (glycol) Diacrylate, polyethylene glycol (glycol) Diacrylate), PAA (polyacrylic acid), and the like.

Further, in some embodiments, in view of the specific physiological functions of the urethra, particularly the increased adhesion of the urethral wall in the case of urethral stricture, the roughness of the urethral mucosa is evident, which results in insufficient contact between the drug coating and the urethral wall and barrier by the adhesion of the mucosal surface when the balloon 110 is inflated, resulting in insufficient effective drug delivery. And according to clinical data, the scar of the urethral stricture tissue is hardened, the tissue layer is too thick, the tissue is dehydrated and dried, and the physiological responsiveness of the tissue is poor, so that the drug permeation and absorption are not facilitated. In some embodiments of the present disclosure, the water-soluble low-crosslinking polymeric auxiliary may include a fifth additive, wherein the fifth additive may include at least one of salicylic acid, allantoin, and lactic acid. In some embodiments, by adding the fifth additive described above, the density of the scar layer and the adherent can be reduced, the moisture binding capacity of the mucosa can be improved, the mucosa keratin can be softened, and the adhesion of the micro-urethral wall can be eliminated, thereby facilitating the transshipment absorption of the drug. In some embodiments, the weight ratio of the fifth additive may be controlled between 0.1% and 15% in order to avoid the aforementioned problems caused by the excessive amount of the fifth additive, considering that the excessive amount of the fifth additive may stimulate the mucosa stress reaction, causing discomfort to the patient, and that the excessive amount of the fifth additive may disturb the ph of the whole coating, thereby affecting the dissociation degree of the drug.

In some embodiments, the drug coating may include the polymer auxiliary agent with low crosslinking degree, the first weakly alkaline additive, the second fat-soluble additive and the drug at the same time, wherein the weight ratio of the drug in the drug coating may be between 35% and 75%, the weight ratio of the polymer auxiliary agent with low crosslinking degree in the drug coating may be between 0.1% and 15%, the weight ratio of the first weakly alkaline additive in the drug coating may be between 0.1% and 45%, and the weight ratio of the second fat-soluble additive in the drug coating may be between 0.1% and 55%.

In some embodiments, the dissolution release time of the drug coating is related to the weight ratio of the aforementioned water-soluble, low-crosslinking polymeric auxiliary in the drug coating. For example, when the weight ratio of the water-soluble polymer auxiliary agent with low crosslinking degree in the drug coating is 1%, the dissolution release time of the drug coating is 3min-4min; for another example, when the weight ratio of the water-soluble polymer auxiliary agent with low crosslinking degree in the drug coating layer is 10%, the dissolution release time of the drug coating layer is 6min to 7min.

In some embodiments, the drug in the foregoing drug coating may include an anti-inflammatory drug and/or an anti-cell proliferation drug. Illustratively, the drug may be any one of paclitaxel, rapamycin, everolimus, tacrolimus, sirolimus, zotarolimus, or a mixture thereof. In some embodiments, to facilitate absorption of the drug substance in the urethral wall, the drug substance selected is required to meet the high lipid solubility characteristics and have a relative molecular mass of no more than 1000 according to the librisky five rule.

In some embodiments, the aforementioned drugs and additives may be dissolved by a solvent to obtain a drug coating solution. Further, the aforementioned drug coating can be obtained by coating the drug coating solution on the outer surface of the balloon 110. In some embodiments, the solvent may include one or more of methanol, ethanol, isopropanol, water, acetone, and the like. It should be noted that the foregoing solvent types are merely illustrative, and in the embodiments of the present disclosure, the solvent or solvent system that can dissolve the drug and add to form a homogeneous mixture can be used to prepare the drug coating solution.

In some embodiments, the aforementioned drug coating solution may be applied to the outer surface of balloon 110 by a spray technique. For example, the drug coating solution may be applied to the outer surface of balloon 110 by ultrasonic spraying, where the power of the ultrasonic spraying may be 0.2W to 3W, a syringe pumpThe flow rate of the drug coating solution can be 0.01 mL/min-1.0 mL/min, the spraying temperature can be 20-55 ℃, and the spraying pressure can be 0.01-0.5 MPa. In some embodiments, the drug concentration in the drug coating obtained after spraying by the spray technique may be 0.5 μg/mm ² ～10μg/mm ² 。

Referring to fig. 2, in some embodiments, a drug coating 111 may be applied to the outer surface of balloon 110. To further reduce the loss of drug coating during delivery, in some embodiments, a hydrophilic protective layer 112 may be provided outside of drug coating 111. In some embodiments, the hydrophilic protective layer 112 may dissolve after a period of time (e.g., 2-5 minutes) under body temperature and a weakly acidic environment until completely removed.

In some embodiments, the aforementioned hydrophilic protective layer 112 may include crystalline sugar or glycans. In some embodiments, the hydrophilic protective layer 112 may be a PVP (Polyvinyl Pyrrolidone ) layer. In some embodiments, the hydrophilic protective layer 112 may be formed by a combination of two or more of crystalline sugar, glycan, and PVP. By providing the hydrophilic protective layer 112 outside the drug coating 111, not only can the drug coating 111 be prevented from being rubbed off from the urethral wall during delivery, but also the drug coating 111 can be prevented from being split during inflation or deflation of the balloon 110, thereby causing the drug coating 111 to be lost. Therefore, in the embodiment of the present disclosure, by providing the hydrophilic protective layer 112 outside the drug and the coating layer 111, the drug loss can be greatly reduced without affecting the drug action to the lesion site, the drug quantity acting to the lesion site can be increased, and the drug transfer rate of the drug-carrying balloon 100 can be further ensured.

In some embodiments, the hydrophilic protective layer 112 may be applied to the outside of the drug coating 111 by spraying, and specific spraying conditions may be referred to in the foregoing, and will not be described herein. In some embodiments, the hydrophilic material (e.g., the aforementioned crystalline sugar or polysaccharide) in the hydrophilic protective layer 112 may be present in a ratio of 0.01mg to 100mg/mL.

In order to verify the effect of drug coatings under different coating conditions and ratios, some examples of the present specification conducted the following experiments:

TABLE 1

Referring to table 1, in some embodiments, it can be seen through a series of experimental searches that the proportion and type of additives in the drug coating (in the examples, the paclitaxel drug is used) have a greater impact on drug transfer and loss results. Referring to number 1 in table 1, when only lipophilic drugs were in the coating, the drugs were difficult to be dissolved by sufficient solvents, the transfer rate was low, and there was much drug remaining on the balloon. With reference to serial numbers 2-4, when the first additive (polyacrylamide is adopted in the embodiment) is introduced into the drug coating, the dissociation degree of paclitaxel in the urethra environment is stabilized, the drug effect and the transfer rate are improved, but with the increase of the content of the first additive, the transfer rate is not obviously improved, and the drug loss rate tends to be increased. Referring to serial numbers 5 to 7, when a second additive (PEG monostearate was used in the examples) was introduced into the drug coating, the drug transfer rate was significantly improved, but as the weight ratio of the second additive was increased to 35%, the drug transfer rate was not significantly improved, and the loss rate was increased. Referring to number 8, when appropriate amounts of the first additive and the second additive are simultaneously introduced into the drug coating, the drug transfer rate is improved to some extent, but there is still a 30% drug loss rate. With reference to serial numbers 9-10, when a high molecular auxiliary agent with low crosslinking degree (polyacrylic acid PAA with low crosslinking degree is adopted in the embodiment) with the weight percentage of 5% is introduced into the drug coating, the dissolution time of the drug is delayed, the loss rate of the drug is greatly reduced, the addition amount is from 5% to 15%, the drug loss can be reduced to 25%, but the slow drug dissolution rate reduces the transfer rate of the drug. Referring to serial No. 11, when the first additive, the second additive and the polymer auxiliary agent with low crosslinking degree are simultaneously introduced into the drug coating system, the drug transfer rate is still maintained above 45%, and the loss rate can be reduced to about 20%. Meanwhile, referring to serial numbers 12 to 13, when a hydrophilic protective layer (PVP layer is used in the example) is loaded on the drug coating, the loss rate of the drug coating can be further reduced.

In some embodiments, the additives incorporated into the aforementioned drug coating may further include a sixth additive that may cause the drug coating to have a positive electrokinetic potential. Specifically, since negative ions on the surface of epithelial cells in the cell membrane cause the cell membrane to present a negative potential, the drug coating can be better transferred or adhered to the lesion site by the attraction of the positive and negative potential after the drug coating has a positive electrokinetic potential by adding a sixth additive to the drug coating. By the attraction of the positive and negative electric potentials, not only the drug dosage transferred to the focus position but also the rate of drug transfer to the focus position can be improved.

In some embodiments, the sixth additive may include at least one ionic polymer. In some embodiments, the sixth additive may preferably be a zwitterionic polymer, such as a glycerophospholipid-based ionic polymer. It should be noted that, in the embodiment of the present specification, the sixth additive may include, but is not limited to, the aforementioned glycerophospholipid-based ionomer. In some other embodiments, the sixth additive may be replaced with other substances having similar or identical properties.

In some embodiments, the electrokinetic potential of the drug coating after addition of the sixth additive may be measured in any suitable manner, for example, electrophoretic light scattering (Electrophoretic Light Scattering, ELS for short) or electroacoustic measurement may be used.

Referring to fig. 3, in some embodiments, balloon 110 in a collapsed state may include a plurality (e.g., 3 or more) of balloon petals, at least two adjacent balloon petals of the plurality of balloon petals being rolled in opposite directions in a collapsed state. In some embodiments, balloon 110 in the plicated state may be first divided into a plurality of petals, each petal She Zaifen being two balloon petals. The aforementioned rolling of adjacent balloon petals in opposite directions in the contracted state may mean rolling of balloon petals on one side of adjacent two petals that are close to each other in opposite directions. As shown in fig. 3, balloon 110 may include a plurality of leaflets 1101. In some embodiments, the leaflets 1101 may be mushroom-shaped, and each leaflet 1101 may include a first balloon valve 1102 and a second balloon valve 1103, wherein the first balloon valve 1102 of one of the adjacent two leaflets 1101 and the second balloon valve 1103 of the other are bent or rolled in opposite directions along the circumference of the inner tube 131 such that a cavity is formed between the adjacent two leaflets 1101 by the first balloon valve 1102 and the second balloon valve 1103. In some embodiments, for the first balloon valve 1102 and the second balloon valve 1103 in the same leaflet 1101, one can be on the inside of an adjacent leaflet 1101 after rolling and the other can be on the outside of an adjacent leaflet 1101 after rolling.

In other embodiments, the first balloon valve 1102 and the second balloon valve 1103 may be independent, i.e., the first balloon valve 1102 and the second balloon valve 1103 may not form the mushroom-shaped valve 1101, and only need to bend or wind the adjacent two balloon valves along the circumferential direction of the inner tube 131 in opposite directions. By adopting the rolling mode, the product size can be reduced to a certain extent, so that the passing performance of the medicine carrying balloon 100 in the process of delivering to the focus position is improved.

In some embodiments, the surface of the balloon 110 may be provided with a drug coating, wherein at least a portion of the drug coating may be disposed in the cavity, thereby protecting the drug coating from drug loss due to contact with the urethral wall during delivery to the lesion site, ensuring a drug dosage delivered to the lesion site, and increasing the delivery rate of the drug-loaded balloon 100 to a certain extent. When the balloon 110 is delivered to the lesion site, the drug coating disposed on the surface of the balloon 110 may be applied to the lesion site by controlling the inflation of the balloon 110.

Referring to fig. 4, in other embodiments, balloon 110 in a pleated condition may include a plurality (three or more) of straight-flap balloon petals 1104, where the plurality of straight-flap balloon petals 1104 may be rolled in the same direction and a cavity may be formed between two adjacent straight-flap balloon petals 1104. Similarly, at least a portion of the drug coating may be disposed within the cavity to protect the drug coating from drug loss due to contact with the urethral wall during delivery to the lesion site, thereby providing more initial drug delivery to the lesion site and facilitating drug delivery and absorption.

To verify drug reloading rates in different situations, the examples of the present specification conducted the following experiments:

example 1: weighing paclitaxel 0.36g, placing in a glass bottle, weighing 10ml of methanol, and oscillating for 30min to obtain uniform mixed solution 1. Then, the solution 1 is sprayed on the saccule by ultrasonic, and the medicine carrying saccule is obtained after drying, and the medicine concentration is 2 mug/mm ² . Finally, balloon winding was performed in the manner shown in fig. 4, to obtain test sample 1.

Example 2: weighing 0.1g of magnesium stearate and 0.36g of taxol, placing in a glass bottle, weighing 10ml of methanol, and oscillating for 30min to obtain a uniform mixed solution 2. Then, the solution 2 is sprayed on the saccule by ultrasonic, and the medicine carrying saccule is obtained after drying, and the medicine concentration is 2 mug/mm ² . Finally, balloon winding was performed in the manner shown in fig. 4, to obtain test sample 2.

Example 3: 0.05g of phosphatidylethanolamine and 0.36g of taxol are weighed and placed in a glass bottle, 10ml of methanol is measured, and ultrasonic oscillation is carried out for 30min, thus obtaining a uniform mixed solution 3. Then, the solution 3 is sprayed on the saccule by ultrasonic, and the medicine carrying saccule is obtained after drying, and the medicine concentration is 2 mug/mm ² . Finally, balloon winding was performed in the manner shown in fig. 4, to obtain test sample 3.

Example 4: weighing 0.1g of magnesium stearate, 0.05g of chitosan and 0.05g of phosphatidylethanolamine, weighing 10ml of methanol, and placing into a glass bottle for ultrasonic oscillation for 30min. After the solution was uniformly mixed, 0.36g of paclitaxel was weighed and placed in a glass bottle, and the mixture was shaken for 30 minutes to obtain a uniformly mixed solution 4. Then, the solution 4 is taken and sprayed on the saccule by ultrasonicDrying to obtain medicine-carrying saccule with medicine concentration of 2 μg/mm ² . Finally, balloon winding was performed in the manner shown in fig. 4, to obtain test sample 4.

Example 5: weighing 0.1g of magnesium stearate, 0.05g of chitosan and 0.05g of phosphatidylethanolamine, weighing 10ml of methanol, and placing into a glass bottle for ultrasonic oscillation for 30min. After the solution was uniformly mixed, 0.36g of paclitaxel was weighed and placed in a glass bottle, and the mixture was shaken for 30 minutes to obtain a uniformly mixed solution 5. 0.1g of polyvinylpyrrolidone is weighed into another glass bottle, 10ml of absolute ethyl alcohol is measured, and the mixture is mixed until the mixture is clear and transparent by ultrasonic oscillation, so as to obtain a solution 6. Ultrasonic spraying solution 5 onto the saccule, spraying solution 6, and drying to obtain medicine-carrying saccule with medicine concentration of 2 μg/mm ² . Finally, balloon rolling was performed in the manner of fig. 4, to obtain a test sample 5.

Example 6: the drug-loaded balloon sprayed in example 5 was taken and rolled up in the manner shown in fig. 3 to obtain a test sample 6.

The test samples 1, 2, 3, 4, 5 and 6 prepared in example 1, 2, 3, 4, 5 and 6 are respectively divided into groups a, b and c, and the group a drug-carrying balloon directly tests the drug content m1; and b, simulating the use process of the drug-carrying saccule in the human urethra by using an in-vitro test model, adopting a pipeline model as a conveying path, and soaking the pipeline by using a buffer solution with pH=6.0. And b, conveying the medicine carrying saccule of the group b to a fixed position through a guide wire, cutting off a saccule part from the tail end of a pipeline, drying, putting into a glass container, adding quantitative acetonitrile, and after ultrasonic oscillation, testing by using a high performance liquid chromatograph to obtain the medicine content m2 on the medicine carrying saccule. c, the medicine carrying saccule of group c is connected to a fixed position through a guide wire, the fixed position is connected with a duck intestine soaked by buffer solution (used for simulating the urethral wall), then the saccule is expanded, the pressure of 10atm is kept for 5min, the medicine carrying saccule is withdrawn, the duck intestine is taken out, dried and soaked by acetonitrile, and subjected to ultrasonic oscillation for 15min, the medicine content of the leaching solution is tested, and the medicine amount m3 of the medicine carrying saccule transferred to the tissue is obtained. The specific results are compared in Table 2 below:

sample number	Transmission loss ratio ((m 1-m 2)/m 1)	Drug transfer rate (m 3/m 1)
			1	18.4％	25.2％
2	37.2％	43.7％
			3	24.5％	27.1％
4	32.6％	39.5％
			5	20.3％	46.3％
6	8.9％	53.8％

TABLE 2

The above-mentioned drug content may be measured by, but not limited to, liquid chromatography.

As can be seen from table 2, test sample 6 had the lowest rate of delivery loss and the highest drug transfer rate. It can be seen that, in the embodiment of the present disclosure, by adding the above-described additive to the drug coating and applying the balloon winding structure shown in fig. 3, the drug loss can be greatly reduced during the balloon delivery process, and the tissue absorptivity can be improved, so that the drug can be better transferred to the tissue during the balloon expansion process, and the focus position can be better treated.

While the basic concepts have been described above, it will be apparent to those skilled in the art that the foregoing detailed disclosure is by way of example only and is not intended to be limiting. Although not explicitly described herein, various modifications, improvements, and adaptations to the present disclosure may occur to one skilled in the art. Such modifications, improvements, and modifications are intended to be suggested within this specification, and therefore, such modifications, improvements, and modifications are intended to be included within the spirit and scope of the exemplary embodiments of the present invention.

Meanwhile, the specification uses specific words to describe the embodiments of the specification. Reference to "one embodiment," "an embodiment," and/or "some embodiments" means that a particular feature, structure, or characteristic is associated with at least one embodiment of the present description. Thus, it should be emphasized and should be appreciated that two or more references to "an embodiment" or "one embodiment" or "an alternative embodiment" in various positions in this specification are not necessarily referring to the same embodiment. Furthermore, certain features, structures, or characteristics of one or more embodiments of the present description may be combined as suitable.

Likewise, it should be noted that in order to simplify the presentation disclosed in this specification and thereby aid in understanding one or more inventive embodiments, various features are sometimes grouped together in a single embodiment, figure, or description thereof. This method of disclosure, however, is not intended to imply that more features than are presented in the claims are required for the present description. Indeed, less than all of the features of a single embodiment disclosed above.

In some embodiments, numbers describing the components, number of attributes are used, it being understood that such numbers being used in the description of embodiments are modified in some examples by the modifier "about," approximately, "or" substantially. Unless otherwise indicated, "about," "approximately," or "substantially" indicate that the number allows for a 20% variation. Accordingly, in some embodiments, numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the individual embodiments. In some embodiments, the numerical parameters should take into account the specified significant digits and employ a method for preserving the general number of digits. Although the numerical ranges and parameters set forth herein are approximations that may be employed in some embodiments to confirm the breadth of the range, in particular embodiments, the setting of such numerical values is as precise as possible.

Each patent, patent application publication, and other material, such as articles, books, specifications, publications, documents, etc., referred to in this specification is incorporated herein by reference in its entirety. Except for application history files that are inconsistent or conflicting with the disclosure of this specification, files that limit the broadest scope of the claims (currently or later in this specification) are also excluded. It is noted that, if the description, definition, and/or use of a term in an attached material in this specification does not conform to or conflict with what is described in this specification, the description, definition, and/or use of the term in this specification controls.

Finally, it should be understood that the embodiments described in this specification are merely illustrative of the principles of the embodiments of this specification. Other variations are possible within the scope of this description. Thus, by way of example, and not limitation, alternative configurations of embodiments of the present specification may be considered as consistent with the teachings of the present specification. Accordingly, the embodiments of the present specification are not limited to only the embodiments explicitly described and depicted in the present specification.

Claims

1. The drug-loaded balloon for urethral stricture is characterized by comprising a balloon and a drug coating arranged on the balloon, wherein the drug coating comprises a drug and an additive, the additive comprises a water-soluble polymer auxiliary agent with low crosslinking degree, a weakly alkaline first additive and a fat-soluble second additive, and the weakly alkaline first additive comprises any one or combination of urea, organic amine, organic alkali, magnesium stearate and calcium stearate.

2. The drug-loaded balloon of claim 1, wherein the water-soluble low-crosslinking polymeric auxiliary comprises at least one of a third additive, a fourth additive, and a fifth additive; wherein the third additive comprises an alkyl fatty group or a group of bile fibers; the fourth additive comprises polyethylene glycol or polyglycerol; the fifth additive includes at least one of salicylic acid, allantoin, and lactic acid.

3. The drug-loaded balloon of claim 1, wherein the fat-soluble second additive comprises one of PEG stearate, phosphatidylethanolamine, dioleoyl phosphatidylethanolamine, amine derivatives of phosphatidylcholine, or a combination thereof.

4. The drug-loaded balloon of claim 1, wherein the water-soluble low-crosslinking polymeric auxiliary agent comprises 0.1-15% by weight of the drug coating, the weakly basic first additive comprises 0.1-45% by weight of the drug coating, the fat-soluble second additive comprises 0.1-55% by weight of the drug coating, and the drug comprises 35-75% by weight of the drug coating.

5. The drug-loaded balloon of claim 1, wherein a hydrophilic protective layer is further disposed on the balloon, the hydrophilic protective layer being wrapped over the drug coating.

6. The drug-loaded balloon of claim 5, wherein the hydrophilic protective layer comprises any one or a combination of crystalline sugar, glycans, and polyvinylpyrrolidone.

7. The drug-loaded balloon of claim 1, wherein the additive further comprises a sixth additive that imparts a positive electrokinetic potential to the drug coating.

8. The drug-loaded balloon of claim 7, wherein the sixth additive comprises a glycerophospholipid ionomer.

9. The drug-loaded balloon of claim 1, wherein the balloon comprises a plurality of balloon petals in a collapsed state, at least two adjacent balloon petals of the plurality of balloon petals being rolled in opposite directions in a contracted state to form a cavity between adjacent balloon petals.

10. The drug-loaded balloon of claim 9, wherein at least a portion of the drug coating is disposed in the cavity.