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wellefare of consumer | Auction | Bargaining
Electronic Commerce Research, 1: 169–181 (2001)  2001 Kluwer Academic Publishers
Internet Advertising, Game Theory and Consumer Welfare
MARCUS CHI-HUNG LING marcus.ling@sunderland.ac.uk Visiting Lecturer, Sunderland Business School, St. Peter’s Campus, University of Sunderland, Sunderland, SR6 0DD, UK KEVIN LAWLER kevin.lawler@sunderland.ac.uk Reader in Industrial Economics, Sunderland Business School, University of Sunderland, Sunderland, SR6 0DD, UK
The aim of this paper is to consider the implications of Internet advertising, for prospective consumer welfare gains/losses. The implications of imperfect information among buyers are discussed to highlight the role of intermediaries and search agents in enhancing consumer welfare in a world of complex products and uncertainty. The argument demonstrates that despite possessing welfare enhancing potential the retailing of complex products on the Internet increases the scope for price discrimination among sellers. Hence, buyers may pay different prices for the same product/services. The paper shows how “agents” may restrict this type of market failure if they possess the ability to search all databases. That the Internet intrinsically exhibits welfare enhancing and reducing characteristic a game model is develop to show how entry of new sellers may proceed or be checked by incumbents. Keywords: Internet advertising, game theory, consumer welfare, Internet economics
1. Introduction When the ﬁrst Internet advertising came out around ﬁve years ago, the direct effects on sales were trivial. In recent years, ﬁrms spent increasing volumes of advertising resources on the Internet to develop e-commerce. The rising trend is phenomenal and is evident in growth rates, rising from $50 million in 1995 to $2.8 billion in 1999 (Table 1). The emerging effects created by Internet advertising are wide-ranging spanning different marketing strategies, which can be illustrated by the expected volume of trade via consumers and businesses (Table 2). In strategic terms, Internet advertising reduces barriers created by geography, thus facilitating the emergence of potential entrants and affecting traditional market shares. With respect to consumer choice, Internet advertising provides a tremendous extra impetus for ﬁrms wishing to practise product differentiation (Ling et al., 1997). Prices are normally vital parameters affecting choice. Ling et al. (1999) uses a game theoretical model to analyse Internet price regimes widely used by Internet retailers. The key implication of this multi-period game shows that time-constrained consumers form rational expectation about prices offered by different Internet retail outlets, and that agents try to
Table 1. Internet advertising revenues. Source: Internet Advertising Bureau (IAB) 2000, + www.Internetnews.com/ On-line advertising (US$ million) 1995 1996 1997 1998 1999 2002 40 266.9 906.5 1,920 2,800* 6,500**
LING, LAWLER
* First three quarters total only. ** Forecast value.
Table 2. Transaction values via the Internet (US$ million). 1995∗ All Consumer Business 100 – – 1996** 500–600 – – 1998+ 32,000 11,200 20,800 2000∗ 168,000 – – 2002+ 425,000 93,500 331,500
Source: ∗ The World in 1997, p. 115. ** The Economist, May 10, 1997. + Nairn (1999).
employ different pricing/advertising strategies to match consumer expectations with price incentives and price-quality relationships. In the subsequent analysis, the major focus is on quality aspects and the economic implications of Internet advertising. A probability analysis is utilised to investigate how agents and ﬁrms may improve the expected payoffs (gains in quality) for consumers in an uncertain world. Furthermore, a game theoretical model is constructed to isolate strategic functions offered by Internet advertising assisting agents’ effort to boost sales. Finally, emergent roles for Internet auctions and advertising are considered. 2. Internet advertising, agent and trade On the Internet, numerous products with varying qualities are advertised and offered to consumers. However, Internet consumers are normally time-constrained and are puzzled by the vast matrix of qualities of goods on sale. Assume that there exists a range of products in a micro-segment environment all with identical selling prices but with different intrinsic qualities. Here quality refers to the “package” including elements such as product design, standard compliance, delivery, and after-sales services. Consumption via the Internet can be seen as a service facilitator when prices on offer are identical. Hence, the well-known Hotelling (1929) model of product differentiation may be applied in serviceoriented situations, where buyers are assumed to be equally distributed along a straight-line horizontal spectrum where ﬁrms are located in different territories to maximise sales. The model predicts that the greater the geographical distance between sellers and buyers, the
higher the time/transaction cost required for delivery or, for waiting for deliveries, and this lowers consumer utilities. The implications of the spatial element are crucial for agent involved in competitive direct marketing via the Internet. For instance, Amazon.com recognises this spatial dimension and consequently has been actively expanding its network of warehouses. The ultimate aim of these outlets is to create a distribution network capable of selling and delivering any item requested by Internet consumers (Tett, 1999). In fact, the prerequisite for efﬁcient delivery is particularly important in areas where consumers are already well served by efﬁcient retailers and good communications infra-structure. At the same time, an efﬁcient business environment implies that Internet retail agents have to face tougher competition being surrounded by traditional retail outlets especially in terms of service qualities and efﬁciency. On the Internet, consumers can search for different categories of goods and services. Nelson (1978) argues that experiential goods are more likely to be affected by advertising than search goods. This is the reason why traditional main media advertising focuses on non-durable and experiential goods/services. However, when advertising costs get cheaper, as advertising space is virtually unlimited on the Internet, there exists many potential opportunities for previously inactive and non-advertised product sectors to advertise on the Internet. However, when more advertising is conducted on the Internet, this creates problems of information overload for buyers. Common knowledge among consumers is extremely limited on the Internet where imperfect knowledge is likely to predominate. Thus, buyers face uncertainty and time-constrained problems when making purchases (Kreps, 1990). To model the informational problems confronting consumers given imperfect knowledge, a simple probability analysis is undertaken. The crucial idea in the example is consistent with the choices offered by used-car markets. Hence, due to lack of information about the true mechanical features of used cars, consumers are thrown into dark and so have to gamble when purchasing. Given that used cars with similar engine characteristics are grouped together, under an identical offer price. Despite the fact that these cars are different in certain quality aspects, sellers who advertise to attract Internet buyers not normally willing to give information on the true mechanical features of cars on offer. Consumers are therefore ignorant of quality levels and do not possess sufﬁcient information to evaluate the potential reliability standards before delivery. This type of buying environment is seen at auction web sites and at used-product supermarkets on the Internet. Retail prices in this analysis are kept identical to facilitate comparisons. However, to reﬂect the varying levels of utilities to be gained by consumers, there exist different perceived buyer values. For instance, we assume that before making a purchase, buyers form the expected mean valuation of that £6000 matches a good quality used car and that £3000 represents a potential ‘lemon’ with low quality. If the market price for all used car models is £5000, consumers are drawn into a gamble. On one hand, if a used car turns out to be of good quality, the purchase is a bargain, representing a £1000 gain. On the other hand, buying a bad quality car results in losses of £2000. In this gambling situation, risk averse consumers will not purchase impulsively and will seek ways to improve their knowledge base. However, any buyers may not have sufﬁcient information/time/ability to make a better choice. As economic search is costly and human beings are often restrained by time, consumers
Table 3. Divergency of users and market values. Users perceived value £6000 £3000 Probability 1/3 2/3 Market price £5000 £5000
Buyers perception Good quality Low Quality
may seek help from intermediaries – search agents, who posses higher levels of expertise and are exposed to more specialised buying techniques. Imagine a situation where an Internet intermediate agent obtains market research information regarding the probability of quality distribution (Table 3). Then they work out a “fair” value for a random purchase, which is £4000 (6000 · 1/3 + 3000 · 2/3). Based on the above “fair” value (£4000), the market price (£5000) implies an average gross proﬁt of £1000 is made on every car sold at Internet site. However, buyers are disadvantaged if they are equipped with insufﬁcient data. To improve payoffs, agents can investigate vehicle histories and make professional judgements accordingly. The agent’s intention is to search for a used car, which has quality at least equivalent to £5000 (good quality as expected by consumers). Obviously, agents can also bargain on behalf of consumers knowing that there is a divergence between the “fair” and market prices. However, price variables are not the major concern of this analysis. This analysis is a simpliﬁed picture of how consumers may be badly served with discriminating pricing practices, and how agents may operate between retailers and buyers. Inevitably, the values of probability distributions help predict market “fair” values. In reality, there are more quality variables forming the formulae for deducing a “fair” price and for other quality evaluations. Indeed, agents equipped with specialised information and marketing techniques will be attentive to special features relating to an optimal consumption choice such as product durability, brand quality, ISO standards and maintenance. The key role played by agents essentially transforms time-constrained consumers into non-time constrained buyers or, eliminates consumer ignorance of potential choices. Agents possess complex databases of quality performance indicators for ranges of products. For instance, within a speciﬁc market subsegment, when consumers specify a range of prospective purchase prices, agents then utilise search technologies to select the mechanise with the highest quality rating. Without such systems organised by search agents, consumers are likely to trade-off time saved against lower merchandise quality. Assuming that the probability distribution in the previous example was reversed between the two quality categories, the resulting “fair” price becomes £5000 (6000 · 2/3 + 3000 · 1/3), which is exactly the same as the market price. If consumers accept to pay this market rate, the role of agents is to ensure that the purchased car is of good quality. This demonstrates the potential welfareenhancing role played by intermediate agents. The issue of incomplete buyer information is crucial for e-commerce, particularly if consumers are sensitive to product quality variations. In traditional economic models, asymmetric information problems normally do not apply to suppliers, hence suppliers on Internet may play a dual role in retailing competition. On one hand, they advertise as much information as possible to match consumer expectations effectively, whereas, on the other hand, they may conceal vital information as evident in the used-car market example; or, they may focus on advertising favourable quality dimensions to motivate sales. Thus, sell-
ers may advertise to strengthen brand image and implicit by-products, such as “goodwill” and generic brand quality. These countervailing economic features arise from the informative and persuasive elements in the advertising process.1 The former is regarded as welfare enhancing while the latter may be wasteful in resources. The two conﬂicting advertising inﬂuences are becoming common on the Internet as sellers invest ever-increasing volumes of advertising outlays at the expense of more traditional advertising media (Ling et al., 1999). The persuasive aspects of advertising are strategically employed to strengthen “brands” and retail value. The “quality” element created by Internet advertising is the “perceived” quality derived from inherited brand “reputation”, recognition and prestige. According to Kreps and Wilson (1982), reputation effects can be easily established. Logically, therefore, the heavier the target advertising becomes the more favourable the perceived quality rating. Consequently, persuasive advertising tends to pull consumers nearer to advertised brands and further away from rival products with less attached advertising. If advertising via the Internet is utilised optimally and follows certain strategic patterns, some ﬁrms are likely to eliminate rivals or obtain higher market shares.
3. A game model for optimal advertising and product entry To examine the realistic interactions between a set of close competitors, a game theoretical approach is employed in the following section. This approaches follows zero-sum game principles, which is a close reﬂection of a mature market rivalry (Kreps, 1991). This analytical approach here allows for the concept of strategic groups to prevail and the product heterogeneity to exist. The game model demonstrated below aims to indicate the optimal allocation of advertising outlays in competitive environments with common knowledge of the prospects of proﬁtable entry. This model enables arch rivals, with equal ﬁnancial strength to tailor advertising strategies to maximise returns in target markets. The following resource matrix represents the “knowledge” of common competitive strategic conditions in the industry. Realising that an established ﬁrm cannot always defend all product categories in the market, potential entrants have an incentive to get into any possible market gap and make proﬁts. To simplify the real world and concentrate on target segments, the model assumes that an incumbent produces two products T1 and T2, yielding a constant unit return of M1 and M2, respectively. Incumbent, however, usually possess more market information and expertise, which allows them to take more exact control over strategic moves. Proﬁt-driven incumbents will choose to maximise returns by concentrating advertising on a product with higher proﬁtability, leaving potential entrants with a credible threat, which minimises their prospects of fruitful entry. This condition is compatible with a classical two player zero sum game. To avoid unnecessary clashes into the incumbent’s target product area, rational
1 The two major economic characters of advertising are supported by two polarised schools of thought.
Stigler (1961), Telser (1964) and Nelson (1974) stress those informative functions of advertising. While Comanor and Wilson (1967), Schmalensee (1972) and Lambin (1976) employ a persuasive view on advertising.
Table 4. An advertising investment matrix. Entrant e A−e Incumbent i A−i
Target products T1 T2
Note: e and i refer to volume of advertising investment (units), A refers to total advertising resource.
Figure 1. The expected payoff for the entrant in product area T1.
entrants tend to take actions after an incumbent does. The potential entrants are followers in a multistage game. If M1 > M2, the incumbent will invest i to enhance sales of T1, allowing A − i for T2 (Table 4). This implicitly assumes that incumbent takes the ﬁrst move and entrants react accordingly based on observed market potential, thus, If i > e, then A − e > A − I. (1)
This implies entrant obtains a payoff of (A − e) − (A − i) M2 = (i − e)M2. (2)
Note. The payoff is assumed to be a multiple of the unit of successful advertising messages (e − i) and the marginal rate of return of advertising messages (M). If an entrant becomes aggressive, with an intention to dominate product market T1, it needs to create sufﬁcient successful advertising messages to eliminate the advertising impact from the incumbent, hence, for e > i, the resulting payoff = (e − i)M1. M1(e − i), if e > i, M2(i − e), if e < i. (3)
Therefore, the overall expected payoff for the entrant is shown as follows: E(e, i) = (4)
Figure 1 shows the payoff matrix for an entrant using a convex function of E(e, i). This indicates that an entrant can get a positive payoff from product from T1, providing its advertising investment volume is above i. However, the primary objective of the incumbent
is to minimise the payoff of potential entrants. This means the incumbent needs to identify its strategic investment for minimising M2(i) and M1(A − i). At i, M2(i) = M1(A − i) ⇒ M2(i) + M1(i) = M1 · A ⇒ i = M1 · A/(M1 + M2). investment i ∗ (5) The location of i in Figure 1 refers to the optimal = M1 · A/(M1 + M2) for defending incumbent’s product territory T1. Based on this probability indicator, the corresponding optimal investment for T2 is M2 · A/(M1 + M2). The model enjoys some degree of ﬂexibility. As proﬁtability changes among product alternatives, the relative ratio [M1/(M1 + M2)] adjusts accordingly to indicate new optimal allocations of advertising outlays among different products. With an optimal strategic advertising game model, incumbents can work out a detailed strategic action plan, which is consistent with the fundamental economic principle of maximising the expected returns in major product areas.
4. Further analysis The use of a game model is to demonstrate that competitions between advertising agents are rational. They act and react with respect to each other’s actions. Advertising very often can affect pricing. Moreover, the cost of advertising can be passed onto consumers. This means that rising competition via expansion of advertising outlays can result in escalating pricing if players cannot optimize their advertising budgets. From the point of view of consumers, unlimited increase in competition via advertising can be socially wasteful, too. Ironically, advertising can be very costly to ﬁrms. Hence, continuous up-scaling of advertising may not be ﬁnancially viable for ﬁrms with smaller marketing budgets. This motivates market players to use advertising budgets strategically in order to trigger different expected responses from market players. Hence, each agent can be expected to act in accordance with certain strategic patterns following game model interactions as described in the previous section. The intention of players for this type of game model is to maximise market share. However, the welfare status of consumers is largely neglected. Internet advertising emerges as a break-though in terms of provision of informative data. Before the Internet era, due to the constraints imposed by the lack of efﬁciency of information exchange and diffusion, asymmetric and imperfect information were the biggest barriers for bridging buyers and sellers. With more intermediate agents serving as ﬁltering processors for ﬁnal data users, the welfare implications of advertising on the Internet become more difﬁcult to be evaluated. This is because quality aspects of advertised merchandises cannot be easily determined by Internet users and even intermediate agents in the short run. Moreover, with the problem of information overload, consumers may collect more irrelevant information and formulate undesirable expectation which may affect their judgement and rational expectation. In the market place, it is common that a seller provides more than one category or type of goods. For instance, big international brewers have been utilising heavy advertising
budget for advancing their market shares. Ling (1998) illustrates brewers can employ advertising to establish long run accumulative effect on sales. Given the fact that brewers are not selling a single type of beer products, their marketing forces have to deal with a proliferation of beers offering for beer drinkers. In terms of market share competition, each of these international brewers is aiming to enhance their existing market share and at the same time each is actively exploring new market potential to strengthen the aggregate market portfolio. With the growth of Internet advertising, many big players have been placing huge budget for the creation of Internet advertising inﬂuences, such as famous brewers like Guinness, Heineken and Asahi. This type of non-price competition, to certain extent, can create puzzling effects on consumption. However, at the same time, Internet advertising represents a strategic inﬂuence to deter or accommodate market entry. As said, the nature of Internet advertising is largely divided into two main categories, one is to highlight its persuasive power for pulling in consumers, while the other is to give better information with respect to advertised products. The role of intermediate agents is more signiﬁcant for the latter as information expertise can facilitate the execution of consumption and enhance the value derived from prospective consumption. Assuming that human beings are constrained by time, the role of intermediate agents can consequently increase the welfare of consumers by providing value-added services for consumers. The process represents a transformation of consumption mode from time-constrained to nontime-constrained. Of course, in our business world, there is a value attached to the respective transformation. Rational consumers requesting services from intermediate agents are supposed to gain a beneﬁt which exceeds, or at most equal to, the cost paid to an agent. Simply, this also represents an improvement of social welfare and in simple term a gain in time cost. For services or consumption processes which can allow the ease of comparison on prices, such as beer prices between international brewers, the role of intermediate agents is less signiﬁcant. However, market players can utilise Internet advertising to reach certain strategic objectives which will be examined in the following section. Concerning the welfare implication of the Internet advertising of the N-product case, the resulting market performance may limit the dimension of future competition. Therefore, Internet can create changing market environment for market players and the structure of competition. These eventually can introduce changing welfare implications such as choice availability and the possibility of practising price discrimination.
5. N -product case In actual markets, ﬁrms usually produce more than one product. With increasing use of product differentiation strategy to penetrate market gaps, a more advanced analysis for sophisticated interactions between product groupings is required. For N-product case, the above theoretical concepts are employed. When an incumbent intends to allocate advertising resources QC for N-products, namely C1 , C2 , . . . , CN , these products also assigned relative proﬁtability values (i.e., the constant marginal return), namely M1 , M2 , . . . , MN , respectively, and where proﬁt indices are arranged in such a way that 0 < M1 < M2 · · · < MN . Assuming that an entrant has QE units of advertising outlay
for promoting target products, namely E1 , E2 , . . . , EN , and QC > QE . The entrant is expected to use a strategy such that, Ei = QE , for i = 1, . . . , N. Similarly, the incumbent will employ a strategy which is of the same format, such that Ci = QC , for i = 1, . . . , N. In economic terms, the resource allocation for each of the C is is to give a best response for each incumbent’s product against the entrant’s attack. The model requires more realistic assumptions if an N-product case is employed for strategic game predictions. First, one unit of incumbent advertising outlay is equivalent to one unit of entrant advertising in terms of absolute advertising inﬂuence on sales. The effect of advertising on competitor’s sales is countervailing. The countervailing remaining inﬂuence depends on the volume of outnumbering units of advertising outlays. To measure successful market penetration power, the higher the number of non-matched attacking messages, the better the resulting penetrating forces to gain market share from the incumbent. Secondly, the payoff for a player is the sum of the resulting penetrations for each of the target products. Hence, for an entrant with products E1 , . . . , EN , the expected payoff is E(EC) = Mi max(0, Ei − Ci ), for i = 1, . . . , N, where, Ei ≥ 0, Ci ≥ 0, Ei = QE and Ci = QC , for i = 1, . . . , N. The resulting outcome is determined by the convex function of E(EC) in C for each E and vice versa. Consequently, the optimal solution consists of a pure strategy for incumbent and a mixed strategy for the entrant. A point consistent with some empirical studies is that since each entrant uses a mixed strategy, it is therefore not rational to attack low proﬁtability product groups. Instead, entrants usually employ random selection strategies and put entire budgets on single products to create greater “outnumbering messages”. In response, the incumbent will always defend the high return product grouping and leave low return items with less protection. If the game is played optimally, incumbent will stay in the market presenting no soft targets for potential entrants. As argued by Friedman (1977), the incumbent must defend her market against a signiﬁcant attack from a single entrant. Ironically, there appears to be chances for entrants in the markets with low returns, however, entrants will obtain less than the value of game if they attack these. With the information on M1 , M2 , . . . , MN , the precise solutions for optimal allocation of advertising can be calculated. In utilising game models and the concept of optimal advertising, a computer programme was generated for calculating the precise ﬁgures for resources used in an entry deterrence game. The simulation results indicate that the Gaussian technique for solving simultaneous systems is able to determine optimal game solutions. This provides more potential avenues for future research in this area.
6. The emerging role of internet commerce The on-line auction web site, e-Bay attracted sales of $307 million in the last three quarters of 1998 and its popularity is expected to achieve $3.2 billion sales in 2002 (Taylor, 1999).2 Rather than providing listed prices for products, this Web site allows people to auction
2 The auction business via the Internet is expected to experience healthy growth as this line of business has
low overheads. In 1998 e-Bay enjoyed gross margins as high as 86% and unlike other on-line businesses, it discovered opportunities for proﬁt and achieved a net income of $19.5 M (Taylor, 1999).
goods and the web sites invite bids from interested parties. The advertising process on this site is more or less like classiﬁed newspaper advertisements, which facilitate the exchange of goods and services. The buying environment allows more negotiation compared to traditional retail markets. The goods sold via this auction site go to the highest bidder. This implies traded prices are set by the highest offer made by potential buyers for every period when offers are agreed. Bakos (1998) argues that web-based auctions reverse the traditional functions of retail markets. Certainly, they provide more complicated matching processes for demand and supply. Apart from e-Bay, there are many other on-line auction sites. For instance, last-minute unsold air-tickets are auctioned by airlines; thus Onsale.com carries out on-line auctions in a way similar to ﬁnancial markets; moreover, Priceline allows prospective bidders to specify requirements for the goods they intend to buy and place offers for auctioned good with participating sellers. In a world puzzled by uncertainty and imperfect information, this auction channel actually converts Internet advertising information into a more powerful strategic tool enhancing the practice of price discrimination. From economic welfare principles, enhanced discriminatory power results in reductions of consumer surplus and increases in sellers’ proﬁts. However, auctions are an efﬁcient way for solving negotiations in one-to many situations. Binmore (1985) uses sequential negotiation processes to demonstrate results of negotiations between rational economic agents recorded at auctions. When transaction costs especially time and communication costs are substantial, auctions eliminate unnecessary inefﬁciency in retail markets. In the case of auctions with reservation prices, Riley and Samuelson (1981) and Myerson (1981) argue that no matter how many bidders exist, sellers impose minimum reservation prices above true values. This phenomenon tends to move equilibrium auction prices away from true equilibria, thus reducing the overall efﬁciency of market institutions. Levin and Smith (1996) argue that competition should serve to enhance the efﬁciency of auctions and to reduce sellers’ incentives to deviate from the efﬁcient valuations. In their earlier studies, Levin and Smith (1994) showed that at auctions with sufﬁcient entry, sellers have no economic incentive to overstate true reservation prices. Due to the fact that Internet commerce focuses on personalisation and customisation services, bargaining processes are essential in determining the payoffs for parties involved in transactions, especially for one-to-one negotiations. The extent to which consumes surplus is extracted depends on the types of bargain, levels of competitive responsiveness and key knowledge of the players. Game theoretical principles can be applied to the bargaining process over the Internet. Relative strengths in bargaining are determined by the relative levels of data owned by parties to the negotiation. The second aspect of a bargaining game concerns the time duration. In most cases in the Internet trade, counter-offers are possible between traded parties. The use of strategic delays in the bargaining game can be employed to signal strengths in the negotiation process. This concept was ﬁrst introduced by Admati and Perry (1987). The use of counter-offers implies that it is possible to generate a series of sequential equilibria during the complex bargaining process as in the models studied by Chatterjee and Samulson (1987). Stronger agents simply wait (strategic delays) for the weak opponent to reply (crack) and then reveal choices, preferences and other decisive elements for the bargain. The number of rounds in the bargaining process depends
on the number of elements needed to be revealed until an opponent cracks. This is typical in one-to-one bargaining processes. In welfare terms, consumers always welcome an “efﬁcient deal” with the lower transaction time costs. In fact this is a crucial service “quality” offered intermediaries. For a one-to-many bargaining regime, the situation is similar to auction trades on-line. If the seller invites bids for speciﬁc contracts of services, the contract falls to the bidder with the best price. However, if the traded good is speciﬁc, search and negotiation are carried out simultaneously, until equilibrium price is reached. In general, sellers may control bargaining processes as they have power to screen all prospective buyers and practise price discrimination implicitly. This may be the reason why prices on Internet are not necessarily lower than goods transacted via traditional retail markets. Bailey and Brynjolfsson (1997) ﬁnd little evidence to support the existence of lower prices in the Internet trading environment compared to normal retail outlets. However, shorter transaction times can be regarded as better quality service provided by the Internet. Moreover, Milgrom (1987) argues that if sellers are able to re-offer an unsold item, there are incentives for them to overstate true values. The sheer size of the Internet marketplace makes it easy to attract potential buyers. This motivates sellers to set reservation prices above the true values, resulting in market failures in some auction markets. However, when the number of bidders falls short of expected/pre-determined levels, reservation prices may be adjusted downwards creating a “ﬂexible reserve” phenomenon as illustrated by Smith (1989). Hence, overstating true product values are not likely in these cases. Smith (1996) argues that auction prices based on “ﬂexible reserve systems” usually relate to objects that have obvious ‘common’ or afﬁliated values. When the number of similar websites increases, the bidding processes and bargaining operations become more competitive. Buyers accumulate more knowledge and form better judgements about assessing market values for good/services sold via the Internet. Therefore, the price of goods sold via these Internet auction web sites should not deviate much from the “perceived” market values in the long run. With regards to Internet commerce utilising agents, Vulkan (1999) argues that there exist suppliers who do not allow their sites to be interrogated by search agents. The technical limitation of inaccessibility restricts the possibility of searching genuine low prices, or better quality services. To a large extent, Internet developments are consumer-driven phenomena. However, central to the potential successes of smart agent Internet shopping are supply-side retailers attitudes towards smart agents. For instance, Yovovich (1995) argues on-line retailers are not amenable to smart search agents entering in their databases.
7. Conclusions The paper has examined the role of imperfect information and “agents” where buyers are time constrained. The potential for the Internet to transform the “knowledge” environment for buyers is clearly cost. However, Internet advertising—like other forms—possesses “persuasive” and informative features. These enhance or reduce consumer welfare potential. Where buyer information is limited, and where common knowledge is restricted the key role of Internet “search agents” is shown a balance to be likely to be welfare in-
creasing. As e-commerce develop the linkages between retailers, agents and consumers may become more complex. Generally, in the long run, as the “knowledge domain” of consumer increases via Internet activity agents will perform a key “quality” service for buyers by matching prices, consumer expectations with “quality” sellers. Proﬁt maximising search agents who fail to do this consistently for consumers with rational expectations will go bankrupt. The consumer driven philosophy of the Internet e-commerce activity will be the dominating feature in Net development in the next ﬁve years. References
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Smith, L. and D. Levin. (1996). “Optimal Reservation Prices in Auctions.” Economic Journal 106, 1271–1283. Stigler, G. (1961). “The Economics of Information.” Journal of Political Economy 72, 213–225. Taylor R. (1999). “Sales Growth Drives Internet Stocks.” Financial Times 38, 28 January. Telser, L. (1964). “Advertising and Competition.” Journal of Political Economy 72, 537–562. Tett G. (1999). “World Stock Market: Fund Piles Weight.” Financial Times. Vulkan, N. (1999). “Economic Implications of Agent Technology and E-commerce.” Economic Journal 109, 67–90. Yovovich, B. (1995). “Smart Agents do the Shopping.” Advertising Age 8, 31 July.
Marcus Ling is a project manager at the Asia Marketing Intelligence Business Consulting in Hong Kong. He is an Applied Economist who has a considerable number of publications on Internet Advertising, the Telecommunications Market, South East Asian Economics and UK Brewing. Dr. Ling worked as a Visiting Lecturer at the University of Sunderland in the UK since 1993. Recently, he has contributed to various chapters to three texts for both undergraduate and post-graduate students.
Kewin Lawler is a Reader in Industrial Economics at the University of Sunderland. His research interests cover all areas of econometrics, especially those connected with application of game theory. He has recently published two texts in these areas. He has supervised a large number of PhD candidates in Economics and Business.
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Patent US5358715 - Enhancement of transdermal drug delivery using monoalkyl phosphates and ... - Google Patents
Pharmaceutical formulations, transdermal drug delivery devices, and methods of drug delivery using the formulations and devices of the invention are disclosed which make it possible to enhance the rate of transdermal drug delivery of pharmaceutically active compounds and in particular molsidomine. The...http://www.google.com/patents/US5358715?utm_source=gb-gplus-sharePatent US5358715 - Enhancement of transdermal drug delivery using monoalkyl phosphates and other absorption promoters
Publication number US5358715 A
Application number US 08/163,817
Also published as EP0746292A1, EP0746292A4, WO1995022950A1
Publication number 08163817, 163817, US 5358715 A, US 5358715A, US-A-5358715, US5358715 A, US5358715A
Inventors Ooi Wong, Thuytien N. Nguyen
Patent Citations (2), Non-Patent Citations (10), Referenced by (17), Classifications (11), Legal Events (8)
Enhancement of transdermal drug delivery using monoalkyl phosphates and other absorption promoters
US 5358715 A
Pharmaceutical formulations, transdermal drug delivery devices, and methods of drug delivery using the formulations and devices of the invention are disclosed which make it possible to enhance the rate of transdermal drug delivery of pharmaceutically active compounds and in particular molsidomine. The rate of drug delivery is increased by using absorption promoters which include monoalkyl phosphates and salts thereof alone or in combination with other absorption promoters such as polyhydroxyl esters, longchain fatty acids, polyhydroxyl alcohols and terpenes. Particular combinations of monoalkyl phosphates with one or more additional absorption promoters provides synergistic effects with respect to enhancing the rate of drug delivery of certain pharmaceutically active drugs such as molsidomine.
a pharmaceutically active drug; and
an absorption promoter in the form of a compound selected from the group consisting of monoalkyl phosphates and pharmaceutically acceptable salts thereof.
2. The formulation of claim 1, wherein the pharmaceutically active drug is molsidomine.
3. The device of claim 1, wherein the alkyl portion of the monoalkyl phosphate or salt thereof contains 8 to 30 carbon atoms.
an additional absorption enhancer selected from the group consisting of a polyhydroxyl ester containing up to 30 carbon atoms; a fatty acid ester containing 8 to 30 carbon atoms; a polyhydroxyl alcohol containing 8 to 30 carbon atoms; and a terpene contain 8 to 30 carbon atoms.
5. The formulation of claim 4, wherein the drug is molsidomine, and the weight ratio of molsidomine to absorption promoter is in the rate of from about 1:99 to about 15:85.
This application is a division of application Ser. No. 07/938,775 filed Sep. 2, 1992, now U.S. Pat. No. 5,308,625.
This invention relates generally to the field of compounds used as permeation enhancers for enhancing the rate of transdermal drug delivery. More specifically, the invention relates to monoalkyl phosphates which, when used alone and/or in combination with other absorption promoters, greatly enhance the transdermal delivery of pharmaceutically active drugs such as molsidomine.
For sometime it has been known that it is possible to administer drugs to a patient by transdermal drug delivery systems. Essentially, the methodology involves placing the drug on the surface of the skin and/or mucous membrane and allowing the drug to permeate through the skin into the patient's blood supply for systemic relief and/or to the specific location where relief is required in order to obtain a local effect. Transdermal drug delivery works well for some drugs and not so well for others which are not readily absorbed through the skin. When a drug is not readily absorbed through the skin, other methodologies and/or compounds can be used in order to enhance the rate of absorption, i.e., get more drug through the skin in a given unit of time.
One well-known method of enhancing the rate of drug delivery is to add an additional component which acts as an absorption promoter, i.e., a compound which enhances the rate of transdermal drug permeation through the skin. Different permeation enhancers operate by different mechanisms. Further, drugs which do not absorb well through the skin are hindered for different reasons. Accordingly, not all permeation enhancers will enhance the permeation of all drugs. The permeation enhancer must be characterized by assisting in overcoming a difficulty which causes the particular drug not to be absorbed well. One drug which is known not to be absorbed well through the skin is molsidomine.
Molsidomine (N-5-ethoxycarbonyl-3-morpholinosydnonimine) is a novel sydnonimine derivative with a mesoionic aromatic ring. It is also an ester prodrug. ##STR1## Molsidomine is a white colorless crystal powder, practically tasteless or odorless. The imine has a molecular weight of 242 with a melting point of 140°-141° C. and a pKa value of 3.34 at 25° C. Its maximum UV absorption wavelength is 326 nm in CHCl3. The solubilities of molsidomine in various solvent systems are shown in Table I.
TABLE I______________________________________Saturated Solubilities of Molsidominein Various VehiclesVehicles         Solubilities at 25° C. (%)______________________________________1      Glycol salicylate                15.12      Propylene glycol                6.373      PEG 400       5.234      Glycerin      1.805      Oleic Acid    1.376      Octyl.decyl oil                0.367      Isopropyl myristate                0.09______________________________________
Reference: Yamada et al., Chem. Pharm. Bull., 35, 3399-3406 (1987).
Freely soluble in CHCl3
Soluble in dil HCl, ethanol, ethyl acetate and methanol
springly soluble in water, acetone, benzene
very slightly soluble in ether, petr ether
Reference: Merck Index, 10th edition, page 892 (1983)
It is soluble in propylene glycol and a variety of organic solvents. The chemical stability of molsidomine has been investigated in detail by Asahi et al. (1971). It is most stable in aqueous solution of pH 5 to 7 (Table II), but is photosensitive, particularly in sunlight.
TABLE II______________________________________Chemical Stability of MolsidominepH              t.sub.90 (days) at 20° C.______________________________________1-2             38 4              2505-7             950     (2.6 years)10              40011              40______________________________________
Reference: Yutaka Asahi, K. Shinozaki, and M. Nagaoka, Chemical & Pharmaceutical Bulletin, Vol 19, 1079-1088 (1971)
Molsidomine has been shown to possess a sustained anti-antinal effect and can be metabolized to SIN-1, which is readily converted into the active metabolite SIN-1A (carries a free nitroso group), Scheme 1. ##STR2##
A very recent investigation on the vasodilation action of molsidomine and other vasodilators, including nitroglycerine reveals that it is the nitric oxide, liberated from the active metabolite SIN-1A, that activates the soluble guanylate cyclase, which in turn causes vasodilation. This is a major difference from the vasodilation action of nitroglycerin.
The coronary vasodilation action of nitroglycerin depends on the presence of cysteine. Cysteine deficiency was found to be associated with tolerance developed for nitroglycerin uses. After prolonged exposure to nitroglycerin, tolerance toward the drug developed in coronary strips can be antagonized by cysteine. However, the active metabolite of molsidomine, SIN-1A, is active in both the presence and absence of cysteine; therefore, molsidomine produces insignificant tolerance (Kulovetz and Holzmann, 1985) making it a better alternative for anti-anginal therapy.
Transdermal delivery of molsidomine has been studied and it has been shown that in an in vivo rat experiment a combination of propylene glycol with 10% oleic acid produced an estimated flux of 399 μg/hr-cm2 for molsidomine.
It has also been shown that a single oral dose of 2 mg of molsidomine can produce anti-anginal effects in patients with coronary heart disease for 3 to 5 hours. Different oral dosing levels can benefit patients with different degrees of coronary heart disease. Typically, it is suggested that oral doses of 2 mg three times daily, or 4 mg four times daily should be given. Pharmacokinetic data indicate that the total clearance and peak plasma concentration of molsidomine were 46,000 ml/hr and 15 mg/ml, respectively, following the administration of an oral dose of 2 mg. The bioavailability of molsidomine from oral doses is 44%. Generally, the effective blood concentration of a drug is less than the peak plasma concentration; therefore, an estimation of target flux based on the effective blood concentration should be a better indication of the delivery rate required to produce therapeutic response.
European patent application 0,127,468, entitled "Percutaneous Pharmaceutical Preparation for External Use," was published Dec. 6, 1984. The application discloses pharmaceutical percutaneous formulations containing various amounts of molsidomine and various absorption promoters.
Transdermal drug delivery devices, pharmaceutical formulations and methods of enhancing the transdermal delivery of pharmaceutically active drugs are disclosed. The invention is particularly directed to such devices, formulations and methods which enhance the transdermal administration of molsidomine using one or more permeation enhancers selected from the group consisting of monoalkyl phosphates and salts thereof combined with one or more of (1) a polyhydroxyl ester; (2) a long chain fatty acid; (3) a polyhydroxyl alcohol; and (4) a terpene.
An important object of the present invention is to provide a transdermal drug delivery device which includes an absorption enhancer in the form of a monoalkyl phosphate and/or salts thereof, alone or in combination with other absorption promoters which promote the absorption of a pharmaceutically active drug and, in particular, the absorption of molsidomine.
Another object of the invention is to provide pharmaceutical formulations comprised of absorption promoters which include monoalkyl phosphates and salts thereof, alone or in combination with other absorption promoters, and a pharmaceutically active drug which is preferably molsidomine.
Another object of the present invention is to provide methods of enhancing the absorption of pharmaceutically active drugs and, in particular, methods of enhancing the absorption of molsidomine using absorption promoters which include monoalkyl phosphates and salts thereof.
An advantage of the present invention is that the rate of absorption of pharmaceutically active drugs and, in particular, molsidomine is greatly increased.
A feature of the present invention is that the transdermal devices and pharmaceutical formulations can be readily formulated utilizing the nontoxic, biocompatible absorption promoter compounds of the invention.
These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the formulation and usage as more fully set forth below, reference being made to the accompanying examples forming a part hereof.
FIG. 1 is a graph showing a standard HPLC chromatogram for molsidomine;
FIG. 2 is a graph showing the skin flux in six different vehicle formulations;
FIG. 3 is a graph showing the permeation enhancement obtained using different combinations of a monoalkyl phosphate as compared with a carrier not containing the monoalkyl phosphate;
FIG. 4 is a graph showing the skin fluxobtained for four different silicone matrices containing different amounts of molsidomine;
FIG. 5 is a graph showing the skin flux obtained with molsidomine using a variety of different skin samples for testing;
FIG. 6 is a graph showing the skin flux obtained with molsidomine formulations of the invention;
FIG. 7 is a graph showing the skin flux obtained with different molsidomine containing formulations of the invention; and
FIG. 8 is a graph showing the skin flux obtained for molsidomine containing formulations of the present invention.
Before the present transdermal drug delivery devices, formulations and methods of drug delivery are described, it is to be understood that this invention is not limited to the particular devices, formulations or methods described as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a monoalkyl phosphate" includes mixtures of such compounds, reference to "an enhancer" includes mixtures of enhancers of the same general type described herein and reference to "the excipient carrier" includes mixtures of, and related types of, excipient carriers generally used by those skilled in the art and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. All publications mentioned herein are incorporated herein by reference in their entirety.
A number of abbreviations standard in this field are used throughout the application and attached figures as follows: CHCl3 for chloroform; PEG for polyethylene glycol; HCl for hydrochloric acid; μl for microliter; μg for microgram; HPLC for high-performance liquid chromatography; NaH2 PO4 for monosodium phosphate; min. for minute; PGML for propylene glycol monolaurate; PG for propylene glycol; DDPO4 for mono-dodecyl phosphate; MOSD for molsidomine; CH3 OH for methanol; H2 O for water; OA for oleic acid; LA for lauryl alcohol.
In order to describe how to make and use the invention, it is most logical to first describe how to make the pharmaceutical formulations of the present invention in that these formulations can be used in making the transdermal drug delivery devices and both the formulations and the devices can be used in carrying out the methods of the invention. The essence of the invention can be understood without reference to the specific examples. However, the examples are provided in order to demonstrate the effectiveness of the claimed invention in enhancing transdermal drug delivery by greatly increasing the rate of drug delivery across the skin. Further, the examples demonstrate the synergistic effect obtained by the use of different combinations of absorption promoters.
In essence, pharmaceutical formulations of the invention include two components which are (1) a pharmaceutically active drug and (2) an absorption promoter. However, the formulations will, in most circumstances, include an additional component (3) in the form of pharmaceutically acceptable excipient carrier.
The pharmaceutically active drug is most preferably molsidomine. Other drugs can be combined with molsidomine in the formulation or substituted for molsidomine. However, if molsidomine is not present, then the pharmaceutically active drug will have a number of characteristics related to molsidomine which allow the drug to be acted upon in the same manner with respect to the absorption promoters and thereby enjoy the benefits of the absorption promoters to substantially the same degree as molsidomine.
The absorption promoter will include a monoalkyl phosphate and/or a salt thereof. A range of different monoalkyl phosphates and salts are disclosed and any one can be used alone or in combination with others in different proportional amounts without affecting the results obtained by the present invention. The main absorption enhancer, which is the monoalkyl phosphate or salt thereof, can be used alone or in combination with one or more additional absorption enhancers which are present within four distinct groups as follows: (1) polyhydroxyl esters; (2) longchain fatty acids; (3) polyhydroxyl alcohols; and (4) terpenes. The additional absorption promoters may be present individually or in any combination of (1)-(4) and each preferably contains about 8 to 30 carbon atoms. The additional absorption promoter may be present in any given amount but is preferably present in an amount substantially greater than the amount by weight of the monoalkyl phosphate absorption promoter, e.g., 2 to 20 times as much.
Pharmaceutical formulations of the present invention preferably include molsidomine (MOSD) as the pharmaceutically active drug. Such formulation preferably comprise about 1-15% MOSD and about 99-85% absorption enhancer (by weight) which is preferably all DDPO4 or a salt thereof. The absorption enhancer such as DDPO4 may be present in a matrix or other carrier and present in a ratio of 1:99 to 20:80 of DDPO4 : matrix and/or vehicle. A particularly preferred formulation includes about 5% MOSD, 10% DDPO4 and 85% PGML. A particularly preferred matrix will include about 6% MOSD, 6% PGML and 88% matrix which is most preferably silicone 2920. All ratios and % amounts are by weight.
The pharmaceutically active drug can be combined with the absorption promoter to form the formulation. However, in order to provide for commercially useful formulations, it is generally desirable to include pharmaceutically acceptable excipient materials which can include water, alcohols and, in particular, lower-chain alcohols such as isopropyl alcohol, various aqueous solutions such as saline solutions, and sucrose solutions, and other liquid excipients known to those skilled in the art, which excipients can be readily determined to mix well with the absorption promoters and pharmaceutically active drugs used in connection with the present invention.
As indicated above, an essential feature of the invention is that it includes a monoalkyl phosphate or salt thereof as an absorption promoter. A range of different monoalkyl phosphates, salts and mixtures of each and/or both can be used. In general, monoalkyl phosphates have the following general structural formula: ##STR3## wherein "n" is in the range of from about 7 to about 29. In one preferred embodiment n is 11, thus providing the following monoalkyl phosphate: ##STR4##
The above structure shows the structure of mono-dodecyl phosphate also referred to as phosphoric acid mono-dodecyl ester which has a melting point in the range of about 58° C. to about 63° C. and a molecular weight of 266. Other monoalkyl phosphates can be used and the alkyl moiety will generally contain 8 to 30 carbon atoms. Any pharmaceutically useful salts of the monoalkyl phosphates can also be used such as sodium and potassium salts.
The monoalkyl phosphates and salts thereof as used in combination with other absorption promoters greatly enhance the transdermal drug delivery rate of pharmaceutically active drugs through biological membranes including the skin, nasal membranes, buccal membranes, rectal membranes, gastric, intestinal and vaginal membranes. Accordingly, the pharmaceutical formulations of the present invention can be placed on any of these membranes in order to enhance the drug delivery rate of drugs through the membrane and into the patient being treated.
In addition to the absorption promoter, the pharmaceutical preparation according to this invention can be compounded with a base component, any alcohol such as benzylalcohol, propylene glycol, sorbitol solution, glycerin, polyethylene glycol, etc., vegetable oils and fats such as olive oil, safflower oil, cottonseed oil, etc., animal oils and fats such as squalene, squalene, lanolin, etc., paraffins such as liquid paraffin, vaseline, etc., higher fatty acid esters such as isopropyl myristate, isopropyl palmitate, diethyl sebacate, glycerin esters such as monoacetin, diacetin, capryltriglyceride, caprintriglyceride, etc., and/or ethyl cellosolve, methyl cellosolve, etc., in suitable proportions, although the preferred proportion of such base component is generally 10 to 95% by weight.
In addition to the absorption promoter and base component mentioned above, the pharmaceutical preparation for percutaneous absorption according to this invention may contain a component for controlling the percutaneous absorption of molsidomine to thereby ensure a sustained blood concentration, such as solid paraffin, beeswax, carnauba wax, hydrogenated castor oil, lanolin, polyethylene glycol (e.g., PEG 400, 1500, 4000), spermwax, glyceryl monostearate, cholesterol, carbopol, carboxymethylcellulose, carboxyethylcellulose, silicone resin, etc., in suitable proportions, although the preferred proportion of such controlling component is generally 10 to 95% by weight.
In accordance with this invention, a pharmaceutical composition for percutaneous absorption containing the aforementioned components can be applied to any human body surface, either as it is or as formulated into any of the hydrophilic, oleaginous and emulsion forms mentioned in the Japanese Pharmacopeia and/or Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (latest edition) incorporated herein by reference.
A particularly preferred formulation contains about 5% molsidomine, 10% monododecyl phosphate and 85% propylene glycol monolaurate.
In essence, the transdermal drug delivery devices of the invention include a support base which is preferably a flexible, substantially planer support material having a pharmaceutically active drug (preferably molsidomine) and an absorption enhancer which includes a monoalkyl phosphate or salt thereof thereon.
The support base may be comprised of a variety of different types of materials. For example, the support base may be comprised of a substantially planer and flexible material which conforms to the shape of the human body when applied to the skin. Such materials may be high molecular weight polymer film such as polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, polytetrafluoro-ethylene, cellulose acetate, cellulose nitrate, polyacrylonitrile, ethylene-vinylalcohol copolymer and polydimethylsiloxane, woven fabric, non-woven fabric composed of, for example, nylon, polyester, polypropylene and polyethylene, paper and so on. The support material is preferably porous such that it has a moisture vapor transmission rate compatible with human skin. Silicone materials are particularly preferred as an absorption matrix into which the drug and absorption promoter are absorbed. Other materials compatible with the skin and capable of absorbing the formulation and releasing it to the skin can also be used.
When the invention is made available in the form of an adhesive tape, sheet or patch, the adhesive agent may be selected from among materials of polyalkylvinylether, polyalkyl acrylate, polyisobutylene, natural rubber, synthetic rubber and so on. Further, for the purpose of importing suitable degrees of plasticity and adhesivity, it is possible to add animal or vegetable oil, vaseline, lanolin or the like, or/and, as an antieruption component, an antihistaminic agent such as diphenhydramine, etc.
In most clinical studies of molsidomine, daily oral dosing of 2 mg for 3 to 4 times has been shown to be effective for the treatment and prevention of anginal pectoris. The total daily dose will be 6 to 8 mg. However, the absolute bioavailability of the molsidomine from oral administration is 44% indicating only 2.64 to 3.52 mg is required to be delivered transdermally; therefore, the target flux for a 20 cm2 molsidomine transdermal therapeutic system is estimated to be about 5.5 to 7.5 μg/hr-cm2.
A particularly preferred device is comprised of about 6% molsidomine, about 6% absorption promoter, and about 88% matrix which is silicone, e.g., silicone 2920. The absorption promoter is most preferably mono-dodecyl phosphate and propylene glycol monolaurate.
In essence, the methods of the present invention involve applying a therapeutically effective amount of the pharmaceutical formulation and/or a transdermal drug delivery device which includes a therapeutically effective amount of the pharmaceutical formulation to the skin and/or mucous membrane of a patient and allowing the formulation or device to remain in place for a sufficient amount of time to deliver a therapeutically amount of a drug to the patient. To obtain a therapeutical effect, the drug must be delivered in sufficient amount at a rate such that a desired effect is obtained. The effect to be obtained, of course, varies depending on the particular drug being delivered. With respect to molsidomine, the effect to be obtained is a vasodilator effect which, if sufficient, relieves angina and/or prevents its occurrence. Accordingly, the effect obtained is systemic. In some instances, the drug being delivered will provide only a local effect. It is most desirable to devise the transdermal drug delivery device so that it can be applied once a day by the patient. This is done in order to maximize patient compliance with an easy-to-follow dosing protocol. In certain circumstances, the pharmaceutical formulation can be applied directly to the skin or mucous membrane by itself or applied and then covered with a conventional bandage.
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the formulations and drug delivery devices of the invention and demonstrate the operability of such and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviation should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
The various materials, methodologies, and formulation components used in connection with the invention are first described in detail followed by a description of various testing procedures.
Molsidomine was obtained from Sigma. Propylene glycol monolaurate (PGML), used in the skin permeation studies, was obtained from Gattefosse (Elmsford, N.Y.). Morstik 607 was obtained from Morton-Thiokol, Silicone 2920 from Dow Corning, and Gelva 2333 from Monsanto. Mono-dodecyl phosphate ester was obtained from Lancaster, N.H.
The concentration of molsidomine in the samples was analyzed by HPLC analytical methods. The HPLC apparatus includes a Perkin-Elmer Diode array detector LC-235, a Perkin-Elmer automatic samples ISS 100C, a Perkin-Elmer pump, and a Quarternary LC pump 620. A column, 100×4.6 mm (ID), packed with Spheri-5-RP-18 (OD-MP) (5 microns) equipped with a guard column, 15×3.2 mm (ID, packed with RP-18, 7 microns) used in the separation was obtained from Applied Biosystems. Several HPLC running conditions have been developed.
A. The mobile phase was 0,025 M NaH2 PO4 (82%): acetonitrile (18%) with a flow rate of 1.0 ml/min, detection wavelength of 315 nm, and retention time of 3.0 min.
B. The mobile phase was methanol (40%) and water (60%) with a flow rate of 1.0 ml/min, detection wavelength of 315 nm and retention time of 2.8 min.
Method (B) has some advantages over that of (A) in that a less expensive solvent, methanol, is used in place of the more expensive acetonitrile, and no phosphate is necessary, which can prolong the column working life. A range of 1 to 55 μg/ml showed linearity in the standard curve. FIG. 1 shows an HPLC chromatogram and a standard curve of molsidomine. For skin flux samples showing high concentration, off-column dilution of the samples is necessary to interpret the concentrations from the standard curves. Molsidomine has been reported to be photosensitive and therefore all the molsidomine solutions were stored in amber vessels.
Solubilities in Vehicles
Molsidomine powder was weighed on weighing paper and transferred into the sample vial. Solvent was transferred into the vial followed by insertion of a small Teflon-coated magnetic stirring bar. The sample vial was screw-capped and placed on top of a multiple stirring system obtained from Florida Scientific, Inc. and housed in an incubation oven at 32° C. The sample solutions were examined for saturation. More molsidomine was added to the solutions until saturation was achieved.
The saturated solutions were filtered through a micro filter to remove excess solid molsidomine. The filtered samples were then assayed for molsidomine concentration by the HPLC analytical method.
Generally, one or two ml of a saturated solution made with a single vehicle or combination of vehicles were prepared for the skin flux experiments. The combination vehicles were first prepared in an amber vial by mixing the proportion of vehicles, and then a small portion of molsidomine powder in the range of 20 to 50 mg was added to the vehicles. The mixtures were stirred with a small magnetic bar and more molsidomine powder was added to the vials as the solid dissolved. In this way, the solubility of molsidomine in the particular vehicle(s) was estimated.
Fabrication of Monolithic Matrices
Each formulation was mixed with a rotatory mixer for at least 1-2 hours until it formed a homogeneous solution or suspension. The mixture was incorporated with various amounts of molsidomine and vehicles. The material was spread evenly on a polyethlyene plastic sheet to make a film with various thickness of 10-40 mils (wet) by a Gardner knife. The film was allowed to dry in a hood for at least 20 minutes and then further dried in an oven at 70° C. After cooling the cured films, a release liner was used to cover the films and they were stored in plastic bags until use.
Basically, the matrix monolithics is a drug-containing matrix layer having a release liner coating on each surface. The release liner is removed from one surface to expose a surface of drug matrix which is applied to the surface of the skin.
EXAMPLE 1 Skin Flux Experiments
Human cadaver epidermis was removed carefully from dermatomed full thickness skin after the skin had been heated in deionized water at 60° C. for one to two minutes. The stripped epidermis was placed between two polyethylene plastic sheets and kept in a refrigerator until use. Discs of the epidermis with diameter of 5/8 inch were punched out with a die and tested for leakage. This was done by first soaking the epidermis in water and then spreading it flat on a plastic sheet, followed by pressing a piece of laboratory tissue on top of the epidermis a few times. Leakages of the epidermis showed wet spots on the tissue.
An epidermis disc was placed on top of the receiver cell of a modified Franz vertical diffusion cell assembly followed by placing the donor cell on top of the receiver cell. A small magnetic stir bar was inserted through the sampling port into the receiver cell compartment. The diffusion cell assemblies were clamped together and transferred to a thermostatted room (32° C.). The receiver cell compartments were filled with 8.0 ml of the isotonic phosphate buffer of pH 5.0. An isotonic phosphate buffer of 7.0 was also used for skin flux comparison. For solution formulations, 0.2 ml of a particular liquid formulation was applied to the donor cell compartments which were then sealed by a Teflon plug. As for matrix formulations, an appropriate size of the matrix discs (diameter of 5/8 inch) were punched with a die. The release liner was removed and the matrix placed onto the epidermis before clamping the diffusion cell assembly together. The weights of the matrix were calculated from the difference in weight between the two release liner discs and the matrix discs. The amount of molsidomine in the donor cell was then calculated. At the appropriate sampling time point, 1.0 ml of sample was replaced by 1.0 ml of fresh buffer.
Skin Flux Data Manipulation
The amount of molsidomine in each sample was assayed by the HPLC analytical methods. Concentration correction for molsidomine is necessary for samples after the second time point of each experiment, since a volume of 1.0 ml of the receiver fluid was removed and this volume was replaced with a fresh receiver fluid. The cumulative amount of molsidomine at each sampling point was calculated and plotted against the sampling time to give the skin permeation profile. The linear portion of the profile was used to estimate the steady state skin flux by linear regression analysis. Division of the slope of the regression line (μg/hr) by the permeation area (usually 0.689 cm2) gives the steady state skin flux (μg/hr-cm2). The acceptability of the skin flux was based on (1) the standard deviation of the experiments (usually triplicated), (2) visual examination of the permeation profiles, and (3) the standard deviations of each data point of all the replicated permeation profiles.
EXAMPLE 2 Primary Rabbit Skin Irritation Study
Primary rabbit skin irritation studies were conducted. The treatments included (1) four molsidomine matrix formulations, (2) a matrix formulation containing silicone 2920 and PGML, and (3) mineral oil as the control. The composition of the matrix formulations are described below.
Saturated Solubilities of Molsidomine
Since the solubilities of molsidomine in many solvents are known, we only determined solubilities of molsidomine in certain vehicles. Table III shows the solubilities in a number of solvent systems. It is soluble in propylene glycol and a solvent combination of propylene glycol with 10% of oleic acid, lauryl alcohol or PGML on the order of 90 mg/ml. In the phosphate buffers, 112 mg/ml was observed. Since the phosphate buffers were used as the receiver fluid, it was important to know if a sink condition could be maintained in each experiment. The solubilities of molsidomine in the phosphate buffer indicate that the receiver fluid can provide a sink condition for all the skin permeation experiments, since the final concentration of molsidomine in the receiver cell is generally less than 2-3 mg/ml.
TABLE III______________________________________Solubilities of Molsidomine in Various SolventsSolvent Systems   Solubilities (mg/ml)______________________________________Propylene Glycol (PG)             85.5 ± 3.9PG:Oleic Acid (10%)             88.1 ± 0.7PG:Lauryl Alcohol (10%)             89.3 ± 1.5PG:PGML (10%)     92.9 ± 2.8Phosphate bufferspH 5.68           12.3 ± 1.8pH 6.80           12.1 ± 1.3______________________________________
Skin Flux from Vehicle Formulations
All the vehicle formulations were saturated with molsidomine; therefore, the thermodynamic activity of molsidomine in these formulations was expected to be maximal. FIG. 2 shows the skin flux of molsidomine from six vehicle formulations. Using propylene glycol alone, the skin flux was rather low; it was comparable to that obtained from a phosphate buffer solution. Very high skin fluxes, on the order of 50 to 75 μg/hr-cm2, were obtained using PGML or a combination or propylene glycol with oleic acid, or lauryl alcohol, or PGML. These high skin fluxes were confirmed in a separate study by using epidermis with lower transepidermal water loss.
______________________________________PG:PGML (9:1)     252.4 ± 47                       μg/hr-cm.sup.2PGML              84.4 ± 2.3                       μg/hr-cm.sup.2______________________________________
Since molsidomine is very stable in aqueous solutions of pH between 5 and 7, it is of interest to see if molsidomine can be delivered from aqueous solutions. A reasonable high skin flux of 9.7±1.9 μg/hr-cm2 was obtained for pH 6.8. This suggests that a hydrophilic matrix such as hydrogel may be a useful reservoir for molsidomine.
In an independent study for matrix formulation made of silicone 2920 (80%), molsidomine (10%) and PGML (10%), using receiver fluids of pH 5.0 or 7.0 has no significant effect on the skin flux of molsidomine.
______________________________________pH         Flux (μg/hr-cm.sup.2)______________________________________5.0        10.6 ± 0.97.0        11.2 ± 0.7______________________________________
A monoalkyl phosphate ester, mono-dodecyl phosphate (DDPO4), which has very low human skin irritation potential, has been tested in the present investigation for skin flux enhancement. FIG. 3 shows the permeation enhancement of molsidomine. Addition of 10% DDPO4 to PGML caused four times increment of skin flux. This absorption promoter also showed pirsidomine skin permeation enhancement.
Skin Flux from Monolithic Matrices
After having achieved high skin flux from solution formulations, matrix formulations were evaluated to determine whether good skin flux can be delivered. The four types of adhesives examined included Silicone 2920, Morstik 607, Gelva 788 and Gelva 2333. FIG. 4 shows the skin flux for four Silicone 2920 matrices loaded with various amounts of molsidomine and PGML. The skin flux appears to be molsidomine concentration dependent.
Since skin permeation variation is unavoidable, different donor skins were tested using a single silicone 2920 matrix formulation. FIG. 5 shows the molsidomine skin flux obtained from a variety of donor skins. The flux ranges from 11 to 20 μg/hr-cm2 with an average of 14.3 μg/hr-cm2. This information is helpful in evaluating the permeability of new donor skin for molsidomine.
Molsidomine can be delivered from Morstik 607 matrices at a flux of 7 μg/hr-cm2 which meets with the target flux as shown in FIG. 6. The skin flux from Gelva 788 matrices is reasonably high as shown in FIG. 7, i.e., is in the range of 10 to 15 μg/hr-cm2. The PGML concentration appears to have some effect on the flux. The skin flux from Gelva 2333 matrices is lower than the previous three types of matrices, ranging from 3.5 to 4.4 μg/hr-cm2 ash shown in FIG. 8.
Table IV shows a summary of skin flux for the best unoptimized matrix formulations evaluated.
TABLE IV______________________________________Molsidomine Monolithic Matrix Formulations              Skin FluxesFormulations       (μg/hr-cm.sup.2)______________________________________Sil 2920/MOSD/PGML 14.3 ± 3.9 80% 10% 10%Gelva 788/MOSD/PGML              15.0 ± 3.9 80% 10% 10%Mstk 607/MOSD/PGML  7.2 ± 1.6 80% 10% 10%Gelva 2333/MOSD/PGML               4.4 ± 0.4 80% 10% 10%Target Skin Flux   5.5-7.3 μg/hr-cm.sup.2______________________________________
Primary Rabbit Skin Irritation
The four best unoptimized matrix formulations were submitted for a primary rabbit skin irritation study. The calculated mean scores are shown in Table V. The formulations, together with the two controls (mineral oil and a matrix made of silicone 2920 and PGML alone), showed zero or very low skin irritation.
TABLE V______________________________________Primary Rabbit Skin Irritation Studyon Monolithic MatricesMatrices           Mean Scores______________________________________Sil 2920/MOSD/PGML 0.28 80% 10% 10%Gelva 788/MOSD/PGML              0.00 82% 10% 8%Mstk 607/MOSD/PGML 0.17 80% 10% 10%Gelva 2333/MOSD/PGML              0.00 80% 10% 10%Sil 2920/PGML      0.28 90% 10%Drakeol 21         0.17(Mineral Oil)______________________________________ Rating: 0 0  Nonirritating 0-1.9  Mildly irritating 2-5.9  Moderately irritating 6-8  Severely irritating
Based on the above-described experiments, it can be determined that molsidomine can be delivered through human cadaver epidermis in a wide range of skin fluxes up to 200 μg/hr-cm2 from some vehicle solutions. Several promising monolithic matrices gave in vitro skin flux ranging from about 5 to 20 μg/hr-cm2, which exceeded the target flux of 5.5-7.5 μg/hr-cm2. A primary rabbit skin irritation study of several monolithic molsidomine matrices showed zero or very low skin irritation scores. Silicone 2920, Gelva 788 and Morstik 607 are potential polymeric materials for developing molsidomine transdermal therapeutic systems.
US4731241 * Mar 9, 1987 Mar 15, 1988 Takeda Chemical Industries, Ltd. Percutaneous pharmaceuticals preparation for external use
1 Kukovetz et al., "Mechanism of vasodilation by molsidomine" American Heart Journal (1985) 109(3):637-640.
2 * Kukovetz et al., Mechanism of vasodilation by molsidomine American Heart Journal (1985) 109(3):637 640.
3 Noack et al., "Molecular aspects underlying the vasodilator action of molsidomine" Journal of Cardiovascular Pharmacology (1989) 14(Supplement 11):S1-S5.
4 * Noack et al., Molecular aspects underlying the vasodilator action of molsidomine Journal of Cardiovascular Pharmacology (1989) 14(Supplement 11):S1 S5.
5 Ostrowski et al., "Pharmacokinetics of molsidomine in humans" American Heart Journal (1985) 109(3):641-643.
6 * Ostrowski et al., Pharmacokinetics of molsidomine in humans American Heart Journal (1985) 109(3):641 643.
7 Schmutzler et al., "Conclusions" American Heart Journal (1985)109(3):723-724.
8 * Schmutzler et al., Conclusions American Heart Journal (1985)109(3):723 724.
9 Takeshita et al., "Long-lasting effect of oral molsydomine on exercise performance" Circulation (1977) 55(2):401-407.
10 * Takeshita et al., Long lasting effect of oral molsydomine on exercise performance Circulation (1977) 55(2):401 407.
U.S. Classification 424/449, 514/946
International Classification A61K9/00, A61F13/00, A61K9/70, A61K47/24
Cooperative Classification Y10S514/946, A61K47/24, A61K9/0014
European Classification A61K47/24, A61K9/00M3

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