CN112807291A

CN112807291A - High-flux transdermal delivery system of nitroglycerin

Info

Publication number: CN112807291A
Application number: CN201911040995.3A
Authority: CN
Inventors: 全丹毅
Original assignee: Jiangsu Jicui New Pharmaceutical Preparation Technology Research Institute Co ltd
Current assignee: Jiangsu Jicui New Pharmaceutical Preparation Technology Research Institute Co ltd
Priority date: 2019-10-30
Filing date: 2019-10-30
Publication date: 2021-05-18

Abstract

The invention relates to a transdermal delivery system controlled to at least 40 [ mu ] g/cm²The transdermal delivery of nitroglycerin is carried out at a higher transdermal rate, preferably for the treatment of, for example, angina pectoris and congestive heart failure, and belongs to the technical field of pharmaceutical preparations. A kind ofNitroglycerin high-flux transdermal drug delivery system capable of reaching 40 mu g/cm on intact human skin²Over hr, and preferably 50-150 μ g/cm²Nitroglycerin was delivered at a rate in the range of/hr. In addition, the ethanol is used as the penetration enhancer of the nitroglycerin and is 500 mu g/cm of 250-²Delivered at a rate of/hr. The rate of delivery of the drug and permeation enhancer is controlled by a controlled release membrane formed of an ethylene vinyl acetate material having a vinyl acetate content greater than 11%, preferably between 12-18%. The system is suitable for treating angina pectoris and congestive heart failure.

Description

High-flux transdermal delivery system of nitroglycerin

Technical Field

The invention relates to a transdermal delivery system controlled to at least 40 [ mu ] g/cm²The transdermal delivery of nitroglycerin is carried out at a higher transdermal rate, preferably for the treatment of, for example, angina pectoris and congestive heart failure, and belongs to the technical field of pharmaceutical preparations.

Background

Nitroglycerin (NG) has long been recognized as a vasodilator and is used to treat angina and congestive heart failure. NG was originally studied orally or buccally, and more recently, transdermally. The NG medicament can be transdermally administered by applying to the skin a gel or ointment, e.g., Nitrobid ointment, which is administered transdermally to the skin at about 0.5 to 0.625 mg/cm²A mean rate of 24 hrs for delivering NG to the body, corresponding to about 20 to 26. mu.g/cm²And/hr. Another system, Deponit, which has been approved in Europe, is at about 15. mu.g/cm²NG was delivered at a rate of/hr.

Although approved products have been widely accepted by patients, the total daily dose of NG delivered from these systems is insufficient to achieve the larger doses required to treat refractory cases in congestive heart failure or angina pectoris. In order to obtain the required daily dose of more than 40mg, it is necessary to use several of the existing systems simultaneously, or to develop systems with a significantly increased administration area, but neither of these methods is acceptable to the patient. Although U.S. Pat. Nos. 4,191,015 and 3,742,951 have been proposed to increase the transdermal rate of NG by increasing the amount of permeation enhancer and U.S. Pat. No. 4,262,003 discloses a method of regulating drug delivery by controlling the delivery of permeation enhancer, we have not achieved this in a way that accurately controls the transdermal rate of NG in vivo to at least 40 μ g/cm²/hr, preferably 50-150 μ g/cm²NG transdermal system/hr.

Disclosure of Invention

It is an object of the present invention to provide a transdermal drug delivery system capable of delivering nitroglycerin through intact skin control at an in vivo transdermal rate of at least 40 μ g/cm 2/hr and for a duration of at least about 16 hours, preferably 24 hours or more.

It is another object of the present invention to provide a nitroglycerin drug transdermal delivery system suitable for treating angina pectoris.

It is another object of the present invention to provide a transdermal nitroglycerin drug delivery system suitable for treating congestive heart failure.

It is another object of the present invention to provide a nitroglycerin transdermal delivery system for co-administering nitroglycerin and its skin permeation enhancer.

NG flux is primarily controlled by the delivery system in order to allow NG to penetrate in the body to the daily NG dose required by the present invention. The NG delivery system must satisfy the following specific conditions.

As used herein, a drug is considered substantially constant if its transdermal rate does not vary by more than about ± 20% during steady state delivery. The steady state transport period is defined as the following part of the total transport time: (a) after the initial phase, the initial phase is characterized by a high rate of penetration into the skin at the beginning; (b) until the NG concentration in the drug depot decreases to below 1 thermodynamic activity of the depot, or the administration is terminated (first-come).

As used herein, the rate of drug permeation in a transdermal delivery system is considered to be system controlled by:

the natural transmission rate Jskin of normal human skin to NG is about 10-50 mu g/cm²In the/hr range, the average is about 40. mu.g/cm²It is therefore clear that the delivery system under the control of the system does not achieve the in vivo drug permeation amounts contemplated herein unless the effective skin permeation rate for nitroglycerin increases significantly over the entire delivery period of the system.

To obtain a systemically controlled transdermal NG delivery system, the NG penetration enhancer must be delivered to the skin at a rate sufficient to enhance penetration of the NG, at least to the Jsystem on the least permeable skin, and preferably to the Jsystem at steady state2.4 times, so that the system control rate of the system is 70 percent. Referring now to fig. 1, the system 1 is preferably manufactured as a multi-layered system with a reservoir consisting of an impermeable backing 2, a NG controlled release membrane 3 attached to the periphery of the impermeable backing 2 but with its central portion separated from the NG controlled release membrane 3 to form the reservoir, an adhesive layer 4 coated on the NG controlled release membrane 3, the adhesive layer 4 carrying a protective and removable backing layer 5, the backing layer 5 being peeled off the system prior to use. Although the preferred embodiment herein uses a system incorporating an adhesive layer 4, there are other means of holding the NG and permeation enhancer delivery system to the skin, including circumferential straps, adhesive covers, straps, buckles, elastic bands, etc. The reservoir is filled with a composition 6, said composition 6 comprising a matrix, preferably a viscous gel or paste, comprising NG and a penetration enhancer. According to the present invention, the interaction between the controlled release membrane 3 and the drug-permeation enhancer reservoir 6 in NG transdermal delivery systems is critical. According to the invention, we have found that if ethanol is to be used to increase the permeability of NG to the desired 40-150. mu.g/cm²In the/hr range, the permeability of the ethanol itself for transdermal delivery is at least about 250 μ g/cm²/hr, preferably higher but not greater than about 500. mu.g/cm²/hr, which is the flux of an unacceptable response to skin after one day of ethanol administration. We have found that the permeability of normal human skin to 95% ethanol is between about 1200 and 1500. mu.g/cm²In the/hr range, therefore, the ethanol Jsystem of the delivery system according to the invention is in the range of about 300 to 750 μ g/cm²Within the range of/hr and 50% of the system control rate, the ethanol permeability is calculated to be 500 mu g/cm²And/hr. We have further found that Ethylene Vinyl Acetate (EVA) membranes having a Vinyl Acetate (VA) content of at least 11%, preferably in the range of 12-18%, have the necessary characteristics to maintain the flux of NG and ethanol within the desired range of the present invention.

In addition, it is necessary to determine the minimum loading of drug and ethanol in the reservoirs so that the delivery system will function to deliver both nitroglycerin and ethanol throughout the intended dosing period, preferably at least about 16 hours. The 16 hour dosing interval allows use when waking up in the morning and can be discontinued before bedtime for normal sleep by removal or loss of the system itself. This regimen is suitable for patients who develop tolerance to NG on continuous use. Systems for 24 hours or longer are used to provide continuous treatment. In both cases, the transdermal delivery system is applied at respective predetermined times to improve compliance.

NG per cm in the system²The minimum loading is determined by the solubility of NG in the reservoir 6 and the rate of transport in vivo, and sufficient NG is required to maintain the thermodynamic activity of the reservoir at a substantially uniform level (saturated solution) throughout the entire transport period. Because the maximum NG delivery rate is controlled by the controlled release membrane 3, ethanol can, but need not, be delivered at a substantially constant rate. However, whether ethanol is delivered at a constant or decreasing rate during NG delivery, the Jsystem of ethanol must be sufficient to maintain the Jskin of NG within a desired range; that is, the Jsystem of ethanol should be at about 300-750 μ g/cm²In the range of/hr. The required flux of ethanol may be achieved during NG if the ethanol is present in sufficient quantities to maintain its thermodynamic activity at no less than about 0.2.

The depot compositions of the present invention comprise a matrix, preferably gelatinous, having low solubility for NG and ethanol, less than about 5mg/gm, in which NG and ethanol are dispersed. We have found that it is difficult, if not impossible, to form stable dispersions of ethanol in conventional NG-hydrophobic carrier matrices, such as silicone oils and polyisobutylene-mineral oil gels, because ethanol is insoluble in such matrices and tends to aggregate into liquid masses therein. In addition, these slugs extract large amounts of dissolved nitroglycerin from NG lactose carrier due to the high solubility of NG in ethanol. We have found that it is necessary to physically adsorb ethanol by a porous support (e.g. colloidal silica), porous polypropylene or any other chemically compatible particle capable of absorbing large amounts of ethanol while maintaining the appearance of a dry powder. The ethanol loaded powder can then be physically mixed with the matrix and prevented from separating. The substrate containing nitroglycerin and ethanol is then contacted at a concentration of at least about 1 and 5mg/cm, respectively²Is filled withFilled into the system, resulting in a system with a minimum administration period of about 16 hours.

In a preferred embodiment of the present invention, medical silicone oil is used as a carrier, colloidal silica is used as a gelling agent, colloidal silica is used as an ethanol absorbent, and an ethylene/vinyl acetate copolymer (EVA) film having a VA content of at least 11% and preferably 12 to 18% is used as a controlled-release film, with a conventional thickness of about 0.001 to 0.003 inches. The higher the VA content of EVA, the greater the permeability to NG and ethanol, in which range the flux of NG and ethanol can be maintained within the desired range. Although anhydrous ethanol is preferred as ethanol, 95% ethanol containing water may be used from the viewpoint of cost. More dilute ethanol solutions may also be used, provided that the ethanol activity must remain above about 0.2 throughout the system life cycle. The lower the initial activity, the lower the initial release rate of ethanol from the system. Thus, with high concentrations of ethanol, the flux of ethanol through the skin during the first short time period is significantly higher than about 500. mu.g/cm²A dilute ethanol solution may be more suitable. In accordance with a general description of our invention, the following specific examples are provided.

Drawings

FIG. 1 is a schematic cross-sectional view of a NG transdermal controlled release delivery system made in accordance with the present invention.

Fig. 2 is a graph of mean NG plasma concentration over time for an NG delivery prior art system and an NG delivery high-throughput system made in accordance with the present invention.

Detailed Description

Example 1

The NG/ethanol depot composition comprises a medical silicone oil matrix gelled with silica, NG uniformly dispersed on lactose, and ethanol adsorbed on a particulate carrier. A gel-like silicone oil was produced by charging 5kg of a medical silicone oil having a viscosity of about 100 centistokes and 175 g of colloidal silica into a high-energy mixer and mixing them. 200 grams of porous polypropylene was charged to another separate container and about 600 grams of USP ethanol (95% ethanol) was added with stirring to produce a flowable powder that was substantially partially dry, with substantially all of the ethanol being visually observed to be absorbed. 5kg of nitroglycerin-lactose (10 wt% nitroglycerin)And porous polypropylene loaded with ethanol were put into the above high energy mixer and mixed until a uniform blend was obtained. The NG-ethanol gel formed was filled in a reservoir between an impermeable backing and a controlled-release membrane, each filled with 2.6 mg/cm using a form-fill-seal machine²And 4.8 mg/cm²NG and ethanol. The backing comprises a medium density polyethylene/aluminized polyester/ethylene vinyl acetate multilayer composite film, and the controlled release film layer in the backing and the other three layers of films is heat-sealed at the periphery of the reservoir. The three-layer film included a release layer formed of a polyester film coated with a release agent, an adhesive layer formed of a silicone medical adhesive, and a controlled release film layer formed of a 1 mil thick EVA (12% VA) film. The system can be manufactured with different sized NG/ethanol release areas, e.g., about 5cm²，10cm²And 20cm². In FIG. 2 is shown a 5cm frame²Systemic application to in vivo plasma concentrations obtained in normal human subjects.

Example 2

A transdermal therapeutic system was manufactured by the process of example 1, except that ethanol was adsorbed on 200g of silica. The release rate was substantially the same as that of example 1.

Example 3

Similar to the system described in example 1, except that instead of an EVA (12% VA) film, an EVA (18% VA) film was used, per cm²Loading 5mg of nitroglycerin and per cm²20mg of 70% ethanol were loaded. The system released nitroglycerin with similar behavior as shown in fig. 2, except that they were about 80% higher flux.

Claims

1. A high flux transdermal nitroglycerin delivery system, comprising:

(a) an impermeable backing;

(b) a controlled release film;

(c) a nitroglycerin-ethanol gel depot between the two, the depot composition comprising a carrier in which the nitroglycerin and ethanol gel are uniformly dispersed;

(d) means capable of maintaining the nitroglycerin and ethanol delivery system transdermal;

the system is characterized by a nitroglycerin permeability of at least 40 μ g/cm 2/hr and an ethanol permeability of about 250-²/ hr。

2. The delivery system of claim 1, wherein: the reservoir comprising nitroglycerin and ethanol in an amount sufficient to deliver at least about 16 hours, the nitroglycerin permeability being in the range of about 50-150 μ g/cm 2/hr, the undissolved ethanol in the nitroglycerin-ethanol reservoir being adsorbed within the particulate carrier; the carrier is silicone oil.

3. The delivery system of claim 1, wherein: the controlled release film is an ethylene vinyl acetate copolymer having a vinyl acetate content of about 11-18%.

4. The delivery system of claim 2, wherein: the steady state permeability of nitroglycerin is substantially constant for a majority of the period, and the steady state permeability of ethanol is in the range of 250-500 μ g/cm 2/hr but in a decreasing trend for a majority of the period; the steady state permeabilities of nitroglycerin and ethanol remained essentially constant for most of the time during the period.

5. A composition suitable for use in a high throughput transdermal nitroglycerin delivery system comprising a carrier having nitroglycerin and ethanol uniformly dispersed therein, said carrier having a solubility for nitroglycerin and ethanol of less than 5mg/g, wherein the amount of ethanol is greater than 50 μ g/g and substantially all of the undissolved ethanol is adsorbed within the pores of the porous particulate adsorbent and is uniformly distributed within the carrier; the porous adsorbent is selected from silicon dioxide and porous polypropylene, and the carrier is silicone oil.

6. A delivery system for high flux transdermal delivery of nitroglycerin through a predetermined area of the skin, comprising in combination:

(a) an impermeable backing;

(b) a controlled release film;

(c) a nitroglycerin-permeation enhancer reservoir between the backing and the membrane, the reservoir comprising a carrier containing nitroglycerin and a skin permeation enhancer both dispersed in the carrier at a concentration higher than their saturation concentration in the carrier; substantially all of the undissolved permeation enhancer is adsorbed in the pores of the porous particulate adsorbent;

(d) means capable of holding said nitroglycerin and ethanol delivery system on the skin.

7. The delivery system of claim 6, wherein: the penetration enhancer is ethanol, the controlled release membrane is an ethylene/vinyl acetate copolymer, the vinyl acetate content of the copolymer is about 11-18%, and the carrier is silicone oil.

8. The delivery system of claim 6, wherein: the dosage of the nitroglycerin and the ethanol is at least 1mg/cm < 2 > and 5mg/cm < 2 > respectively.

9. The delivery system of claim 6, wherein: the means for holding the system on the skin is to place a nitroglycerin and permeation enhancer permeable adhesive layer between the membrane and the skin.

10. The delivery system of claim 1, wherein: the means by which the system is held on the skin is by placing a nitroglycerin and ethanol permeable adhesive layer between the membrane and the skin.